Affinage

MCPH1

Microcephalin · UniProt Q8NEM0

Length
835 aa
Mass
92.8 kDa
Annotated
2026-04-28
98 papers in source corpus 39 papers cited in narrative 39 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MCPH1 (microcephalin/BRIT1) is a multi-BRCT-domain protein that serves as a central coordinator of chromosome condensation, DNA damage signaling, and neuroprogenitor cell division. Its C-terminal tandem BRCT domains bind γH2AX (recognizing both pSer139 and pTyr142) to recruit the SWI-SNF chromatin remodeling complex and stabilize RAD51-ssDNA filaments at double-strand breaks, thereby promoting homologous recombination repair and class-switch recombination (PMID:17925396, PMID:22908299, PMID:19525936, PMID:32735676, PMID:28724724); its N-terminal BRCT domain and central region inhibit condensin II by binding the NCAPG2 subunit during interphase, preventing premature chromosome condensation, through a mechanism analogous to WAPL-mediated cohesin regulation (PMID:16434882, PMID:34850681, PMID:21911480). In neuroprogenitors, MCPH1 couples the centrosome cycle to mitotic entry via centrosomal Chk1 and βTrCP2-mediated Cdc25 degradation, and its loss causes premature asymmetric division and primary microcephaly in mice (PMID:21947081, PMID:29150431). MCPH1 protein levels are controlled by CDK1-dependent phosphorylation and APC/C-Cdh1-mediated degradation through isoform-specific D-box and KEN-box degrons, while KAT7-mediated acetylation of its NLS regulates nuclear–cytoplasmic partitioning, with cytoplasmic MCPH1 additionally suppressing necroptosis by sequestering phospho-RIPK3 in hematopoietic stem cells (PMID:30303738, PMID:29150431, PMID:38632351).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2005 High

    Establishing MCPH1/BRIT1 as a DNA damage checkpoint protein resolved its role beyond neurogenesis, showing it is required for intra-S and G2/M checkpoint activation and expression of key repair factors BRCA1 and Chk1.

    Evidence RNAi knockdown with checkpoint assays and γH2AX foci colocalization after ionizing radiation in human cells

    PMID:16217032

    Open questions at the time
    • Mechanism of transcriptional control of BRCA1/Chk1 by MCPH1 not defined
    • Direct vs. indirect role in checkpoint signaling unclear
  2. 2006 High

    Identifying condensin II as the effector of premature chromosome condensation in MCPH1-deficient cells established that MCPH1 is a negative regulator of condensin II, not a general chromatin factor.

    Evidence siRNA depletion of condensin I vs. condensin II subunits in MCPH1 patient cells, with PCC rescue only by condensin II depletion; parallel DDR foci colocalization studies

    PMID:16434882 PMID:16872911

    Open questions at the time
    • Physical interaction between MCPH1 and condensin II not yet demonstrated
    • Mechanism of inhibition unknown
  3. 2007 High

    Mapping the γH2AX-binding activity to MCPH1's C-terminal tandem BRCT domains and centrosomal localization to the N-terminal BRCT domain delineated the modular architecture underlying its dual functions in DDR and centrosome biology.

    Evidence In vitro phospho-peptide binding assays, BRCT domain deletion mutants tested in H2AX-/- and MDC1-depleted DT40 cells; Drosophila mcph1 null mutant epistasis with Chk2

    PMID:17599047 PMID:17895362 PMID:17925396

    Open questions at the time
    • Structural basis of γH2AX recognition not yet resolved
    • How centrosomal localization links to condensation control unknown
  4. 2008 High

    Demonstrating that MCPH1 physically associates with condensin II via the CAPG2/NCAPG2 subunit and cooperates with E2F1 on damage-response gene promoters revealed two distinct interaction modes — one controlling chromosome structure and one controlling transcription.

    Evidence Reciprocal Co-IP with domain mapping in MCPH1-/- MEFs; ChIP and promoter reporter assays for E2F1-MCPH1 cooperation on CHK1, BRCA1, RAD51 promoters

    PMID:18660752 PMID:18718915

    Open questions at the time
    • Direct inhibitory mechanism on condensin II enzymatic activity not reconstituted
    • E2F1-MCPH1 cooperation not validated in vivo
  5. 2009 High

    Discovering that MCPH1 recruits SWI-SNF chromatin remodelers to DNA lesions via ATM/ATR-phosphorylated BAF170 established the mechanism by which MCPH1 promotes chromatin relaxation to facilitate downstream repair, and the N-terminal BRCT crystal structure identified a critical hydrophobic pocket for condensation control.

    Evidence Co-IP and chromatin fractionation after IR for SWI-SNF recruitment; 1.6 Å crystal structure of N-terminal BRCT with mutagenesis and complementation in Mcph1-/- MEFs

    PMID:19525936 PMID:19925808

    Open questions at the time
    • Whether SWI-SNF recruitment and condensin II inhibition are functionally linked is unknown
    • Structural basis of condensin II binding not resolved
  6. 2010 High

    MCPH1 knockout mice revealed essential in vivo roles in homologous recombination (through RAD51/BRCA2 recruitment), meiosis, and limiting IR-induced centrosome amplification, extending cell-based findings to organismal physiology.

    Evidence Mcph1-/- mice with IR sensitivity, RAD51 foci quantification, meiotic chromosome analysis, Co-IP with RAD51/BRCA2; DT40 knockout centrosome electron microscopy

    PMID:20107607 PMID:20661222

    Open questions at the time
    • Separation of centrosome and DDR functions in vivo not achieved
    • Direct biochemical role of MCPH1 in RAD51 filament formation not tested
  7. 2011 High

    A convergence of studies resolved how MCPH1 controls neuroprogenitor division (via Chk1-centrosome-Cdk1-Cdc25b axis), how its N-terminal domain directly inhibits condensin II chromosomal loading, and identified SET as a co-factor and the tandem BRCT-γH2AX co-crystal structure.

    Evidence Conditional KO mice with Cdc25b shRNA rescue in neocortex; Xenopus egg extract condensation reconstitution; SET Co-IP with mutagenesis; crystal structures of C-terminal BRCTs with γH2AX and Cdc27 peptides

    PMID:21515671 PMID:21911480 PMID:21947081 PMID:22139841 PMID:22154951

    Open questions at the time
    • How MCPH1 inhibits condensin II loading mechanistically (gate-opening vs. competition) not distinguished
    • Physiological relevance of Cdc27 binding to cell cycle control unclear
  8. 2012 High

    Dual phosphorylation reading of H2AX (pSer139 + pTyr142) by MCPH1 BRCT domains refined the γH2AX recognition model, while isoform characterization showed both MCPH1 variants rescue condensation defects but only full-length localizes to damage foci.

    Evidence Crystal structure with biochemical and cellular recruitment assays for dual-mark reading; RT-PCR isoform mapping with siRNA complementation

    PMID:22908299 PMID:22952573

    Open questions at the time
    • Relative contributions of isoforms to brain development unknown
    • Whether pTyr142 reading affects downstream repair pathway choice untested
  9. 2015 High

    Identifying the BRUCE-USP8 deubiquitination axis as a prerequisite for MCPH1 recruitment to DSBs revealed a K63-ubiquitin-based regulatory layer controlling MCPH1 availability at damage sites.

    Evidence Co-IP, ubiquitination assays, and foci formation in BRUCE-mutant mouse model; UBC domain mutagenesis

    PMID:25733871 PMID:26683461

    Open questions at the time
    • E3 ligase responsible for K63-ubiquitination of MCPH1 not identified
    • Whether deubiquitination regulates condensin II inhibition function unknown
  10. 2017 High

    Demonstrating that MCPH1 promotes βTrCP2-mediated Cdc25A degradation independent of DNA damage and is itself degraded by APC/C-Cdh1 unified the cell-cycle regulation of MCPH1 with its neuroprogenitor division control function.

    Evidence Co-IP, Cdc25A degradation assays, neuroprogenitor in vivo rescue, APC/C substrate specificity mapping

    PMID:29150431

    Open questions at the time
    • Whether Cdc25A degradation function contributes to microcephaly pathogenesis specifically tested only in one model
    • Temporal coordination of MCPH1 degradation with condensin II regulation not resolved
  11. 2020 High

    Reconstitution with purified proteins proved MCPH1 directly binds DNA and stabilizes RAD51-ssDNA filaments ~2-fold, while the MCPH1-TRF2 co-crystal revealed a telomere-specific repair function promoting replication fork restart at dysfunctional telomeres.

    Evidence Single-molecule tethered particle motion with recombinant MCPH1 and RAD51; crystal structure of MCPH1-TRF2 TRFH complex with telomere FISH and DNA fiber analysis

    PMID:32735676 PMID:33203878

    Open questions at the time
    • Whether RAD51 filament stabilization and SWI-SNF recruitment act in parallel or sequentially is unknown
    • In vivo telomere-specific function not tested in MCPH1-deficient organism
  12. 2021 High

    Hi-C and chimeric protein experiments in MCPH1-deleted ES cells established that MCPH1 inhibits condensin II via binding NCAPG2 analogously to WAPL-cohesin regulation, and that unleashed condensin II enhances A/B compartment mixing independent of CDK1.

    Evidence Mcph1-deleted mouse ES cells, Hi-C, CDK1 inhibition, SMC2-NCAPH2 fusion abrogating MCPH1 inhibition

    PMID:34850681

    Open questions at the time
    • Short linear motif in MCPH1 that binds NCAPG2 not structurally resolved
    • Whether MCPH1 acts as a gate-opener or competitive inhibitor not biochemically distinguished
  13. 2024 High

    KAT7-mediated acetylation of the MCPH1 NLS during aging revealed a post-translational switch controlling nuclear–cytoplasmic partitioning, and cytoplasmic MCPH1 was shown to suppress necroptosis by binding p-RIPK3 in hematopoietic stem cells.

    Evidence HSC fractionation, KAT7 acetylation assay, NLS lysine mutant analysis, Co-IP with p-RIPK3, necroptosis assay

    PMID:38632351

    Open questions at the time
    • Whether p-RIPK3 binding occurs in non-hematopoietic tissues unknown
    • Deacetylase counteracting KAT7 on MCPH1 NLS not identified
    • Whether cytoplasmic MCPH1 pool contributes to condensin II regulation not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of MCPH1's direct inhibition of condensin II via the NCAPG2 subunit — whether it acts as a ring-opener or competitive chromosomal loading inhibitor — and how its multiple functions (DDR, condensation, centrosome, necroptosis) are coordinated in a single cell cycle remain unresolved.
  • No high-resolution structure of MCPH1-condensin II complex
  • Relative contribution of each MCPH1 domain to microcephaly pathogenesis not separated in human genetics
  • Whether MCPH1's necroptosis-suppressing and DDR functions are mutually exclusive in vivo is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0042393 histone binding 3 GO:0060090 molecular adaptor activity 3 GO:0140110 transcription regulator activity 3 GO:0003677 DNA binding 2
Localization
GO:0005634 nucleus 4 GO:0005694 chromosome 3 GO:0005815 microtubule organizing center 2 GO:0005829 cytosol 1
Pathway
R-HSA-73894 DNA Repair 7 R-HSA-1640170 Cell Cycle 6 R-HSA-1266738 Developmental Biology 3 R-HSA-4839726 Chromatin organization 2 R-HSA-168256 Immune System 1 R-HSA-5357801 Programmed Cell Death 1
Partners
BRUCEBTRC2E2F1NCAPG2RAD51SETSMARCC2TRF2
Complex memberships
BRUCE-USP8-BRIT1SWI-SNF

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 BRIT1/MCPH1 is required for activation of both the intra-S and G2/M DNA damage checkpoints; it is a chromatin-associated protein that forms irradiation-induced nuclear foci colocalizing with γ-H2AX, and is required for expression of BRCA1 and Chk1 and phosphorylation of Nbs1. RNAi knockdown, nuclear foci immunofluorescence, Western blot, cell cycle checkpoint assays after ionizing radiation Proceedings of the National Academy of Sciences of the United States of America High 16217032
2006 BRIT1/MCPH1 forms nuclear foci within minutes of irradiation that colocalize with 53BP1, MDC1, NBS1, ATM, RPA, and ATR; BRIT1 is required for activation of these proximal DNA damage response elements; its depletion increases chromosomal aberrations. Immunofluorescence foci colocalization, RNAi depletion, metaphase spread chromosomal aberration assay Cancer cell High 16872911
2006 Premature chromosome condensation (PCC) in G2 and delayed decondensation in MCPH1-deficient patient cells is mediated by condensin II; siRNA depletion of condensin II subunits (but not condensin I) rescues the condensation defects in MCPH1 patient cells. siRNA depletion of condensin subunits in MCPH1 patient cells, cell cycle analysis Cell cycle (Georgetown, Tex.) High 16434882
2007 MCPH1 is recruited to DNA double-strand break sites via its C-terminal tandem BRCT domains binding phosphorylated H2AX (γH2AX); this recruitment is H2AX-dependent but MDC1-independent; MCPH1 binds a phospho-H2AX peptide in vitro with affinity similar to MDC1. In vitro phospho-peptide binding assay, foci formation in H2AX-/- and MDC1-depleted cells, BRCT domain mutant analysis The Journal of biological chemistry High 17925396
2007 In chicken DT40 cells, MCPH1 N-terminal BRCT1 domain is required for centrosomal localization throughout the cell cycle, while C-terminal tandem BRCT2/BRCT3 domains are required for ionizing radiation-induced nuclear foci formation via interaction with γ-H2AX. Domain deletion mutant analysis, immunofluorescence, foci formation in ATM/Brca1/H2AX-deficient cells Oncogene High 17599047
2007 Drosophila MCPH1 is required for genomic stability in early embryo S-M cycles; loss of mcph1 causes mitotic arrest with barrel-shaped spindles and chromatin bridging; Chk2 mutation suppresses these defects, placing MCPH1 upstream of Chk2-mediated checkpoint. Drosophila genetic screen, null mutant analysis, epistasis with Chk2 mutation, live imaging Journal of cell science High 17895362
2008 MCPH1 physically associates with the Condensin II complex; this interaction is mediated by the CAPG2 subunit of Condensin II binding to a middle domain (residues 376–485) of MCPH1; this interaction is required for homologous recombination repair. Co-immunoprecipitation, domain mapping, siRNA depletion, HR repair assay in MCPH1-/- MEFs The Journal of biological chemistry High 18718915
2008 MCPH1 cooperates with E2F1 by interacting with it on the promoters of CHK1, BRCA1, RAD51, DDB2, TOPBP1, p73, and caspase genes to activate DNA repair, checkpoint, and apoptosis pathways; MCPH1 forms oligomers through its second and third BRCT domains. Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), promoter reporter assays, dominant-negative mutant analysis EMBO reports High 18660752
2009 After DNA damage, BRIT1/MCPH1 increases its interaction with the SWI-SNF chromatin remodeling complex (specifically BAF170 subunit) through ATM/ATR-dependent phosphorylation of BAF170; BRIT1 recruits SWI-SNF to DNA lesions to promote chromatin relaxation and facilitate DNA repair. Co-immunoprecipitation, chromatin fractionation, RNAi knockdown, chromatin relaxation assay Nature cell biology High 19525936
2009 The N-terminal BRCT domain of MCPH1 contains a hydrophobic pocket (adjacent to an elongated β1-α1 loop) that is required to prevent premature chromosome condensation; mutations in this pocket abrogate rescue of PCC in MCPH1-/- MEFs; the disease-associated T27R mutation resides in this domain. X-ray crystallography (1.6 Å resolution), site-directed mutagenesis, complementation assay in Mcph1-/- MEFs Journal of molecular biology High 19925808
2010 BRIT1/MCPH1 knockout mice are hypersensitive to γ-irradiation, exhibit severe chromatid breaks, reduced RAD51 foci, impaired meiotic homologous recombination, and infertility; BRIT1 binds RAD51/BRCA2 complexes and its absence impairs chromatin recruitment of RAD51 and BRCA2. Knockout mouse model, irradiation sensitivity, metaphase spread, RAD51 foci, meiotic chromosome analysis, Co-immunoprecipitation PLoS genetics High 20107607
2010 MCPH1/BRIT1 limits ionizing radiation-induced centrosome amplification; Mcph1-deficient DT40 cells show massive centrosome amplification after IR with sustained Chk1 phosphorylation and dysregulated Cdk2 activity, suggesting MCPH1 controls centrosome numbers after DNA damage. Mcph1 knockout in DT40 cells, light and electron microscopy of centrosomes, Western blot for pChk1 and Cdk2 activity Oncogene Medium 20661222
2011 MCPH1 deletion in mice causes primary microcephaly through premature switching of neuroprogenitors from symmetric to asymmetric division; MCPH1 deficiency abrogates Chk1 localization to centrosomes, causing premature Cdk1 activation and early mitotic entry, which uncouples mitosis from the centrosome cycle and misorients the mitotic spindle; silencing Cdc25b rescues spindle misalignment and premature neurogenesis in Mcph1-KO neocortex. Conditional knockout mice, centrosome immunofluorescence, spindle orientation analysis, Chk1 localization assay, in vivo Cdc25b shRNA rescue Nature cell biology High 21947081
2011 An N-terminal domain of hMCPH1 specifically inhibits condensin II by competing for its chromosomal binding sites in vitro; the central domain of hMCPH1 plays an auxiliary role in shaping metaphase chromosomes by physically interacting with condensin II; the N-terminal domain alone is sufficient to rescue the PCC phenotype in patient cells. Xenopus laevis egg extract cell-free condensation assay, patient cell complementation, domain deletion analysis The Journal of cell biology High 21911480
2011 SET nuclear oncogene is a direct binding partner of the MCPH1 N-terminal BRCT domain; SET knockdown causes abnormal chromosome condensation similar to MCPH1-deficient cells; condensin II knockdown rescues SET-depleted chromosome condensation phenotype; MCPH1 V50G/I51V missense mutations impair SET binding and fail to rescue PCC in Mcph1-/- MEFs. Co-immunoprecipitation, RNAi knockdown, complementation in Mcph1-/- MEFs, epistasis with condensin II The Journal of biological chemistry High 21515671
2011 VIP blockade during neurogenesis specifically downregulates Mcph1 expression, leading to downregulation of Chk1 and reduction of Chk1 kinase activity; in vitro silencing of either Mcph1 or Chk1 in neurospheres mimics VIP antagonist-induced inhibition of cell proliferation, placing MCPH1 in a VIP/MCPH1/Chk1 signaling axis. Quantitative RT-PCR, Western blot, Chk1 kinase assay, siRNA knockdown in neurospheres The Journal of clinical investigation Medium 21737879
2011 Crystal structure of MCPH1 C-terminal tandem BRCT domains in complex with a γH2AX tail reveals binding selectivity for pSer+3 and preference for phosphopeptide with free COOH-terminus; fluorescence polarization assays confirm the binding parameters. X-ray crystallography, fluorescence polarization binding assay Journal of structural biology High 22154951
2011 MCPH1 C-terminal tandem BRCT domains bind Cdc27, a component of the APC/C, in a phosphorylation-dependent manner; crystal structure of MCPH1 C-BRCTs in complex with phosphorylated Cdc27 peptide was determined; interface mutations disrupt the interaction. X-ray crystallography, in vitro and in vivo binding assays, site-directed mutagenesis The Journal of biological chemistry High 22139841
2012 MCPH1 tandem BRCT domains can simultaneously read both pSer139 and pTyr142 modifications on H2A.X; structural, biochemical, and cellular evidence shows MCPH1 is recruited to DNA damage sites via both states of H2A.X phosphorylation. Crystal structure, biochemical binding assays, cellular recruitment analysis Proceedings of the National Academy of Sciences of the United States of America High 22908299
2012 MCPH1 encodes two major isoforms (full-length MCPH1-FL and MCPH1Δe9-14) with distinct regulation; both isoforms have nuclear localization mediated by separate NLS motifs and both complement the chromosome condensation defect in MCPH1-deficient cells; MCPH1-FL but not the short isoform localizes to γH2AX foci after irradiation. RT-PCR isoform characterization, nuclear localization assay, siRNA complementation, immunofluorescence after irradiation PloS one Medium 22952573
2014 Drosophila MCPH1-B isoform is a substrate of APC/CCdh1 E3 ubiquitin ligase; degradation requires an N-terminal D-box motif; dMCPH1-B is directly ubiquitinated by reconstituted APC(Cdh1) in vitro; overexpression of hMCPH1 in Xenopus embryos disrupts cell division. Xenopus egg extract degradation assay, D-box mutagenesis, reconstituted ubiquitination assay, Xenopus embryo overexpression Biology open High 24972868
2015 BRIT1/MCPH1 is K63-ubiquitinated in unstimulated cells; BRUCE acts as a scaffold bridging USP8 and BRIT1 to form a nuclear complex; BRUCE promotes USP8-catalyzed deubiquitination of BRIT1 as a prerequisite for BRIT1 recruitment to DSB sites via γ-H2AX; loss of BRUCE or USP8 impairs BRIT1 deubiquitination and foci formation. Co-immunoprecipitation, ubiquitination assay, foci formation analysis, homologous recombination repair assay, BRUCE-mutant mouse model Proceedings of the National Academy of Sciences of the United States of America High 25733871
2015 BRUCE UBC domain (E3 ligase activity) is required for USP8-mediated deubiquitination of BRIT1 and its subsequent recruitment to DSBs; UBC domain mutation does not disrupt BRUCE-USP8-BRIT1 complex formation but impairs deubiquitination and DSB signaling. Domain mutagenesis, Co-immunoprecipitation, ubiquitination assay, HR repair assay PloS one Medium 26683461
2013 BRIT1/MCPH1 regulates p53 protein stability by blocking MDM2-mediated ubiquitination of p53; knockdown of BRIT1 in normal breast epithelial cells caused oncogenic transformation. Co-immunoprecipitation, ubiquitination assay, p53 stability assay, cellular transformation assay Carcinogenesis Medium 23729656
2014 BRIT1 phosphorylation at Ser-322 (by ATM or ATR upon replication stress) facilitates efficient recruitment of TopBP1, a key ATR activator, to DNA damage sites; BRIT1 is dispensable for initiation but essential for amplification of ATR signaling. Co-immunoprecipitation, phospho-mutant analysis, TopBP1 recruitment assay, ATR signaling assays The Journal of biological chemistry Medium 25301947
2017 MCPH1 interacts with and promotes E3 ligase βTrCP2 to degrade Cdc25A independent of DNA damage; this controls mitotic entry of neuroprogenitors; MCPH1 itself is degraded by APC/CCdh1 (not APC/CCdc20) in late mitosis and G1; forced MCPH1 expression causes cell death, showing importance of its timely degradation. Co-immunoprecipitation, Cdc25A degradation assay, neuroprogenitor in vivo rescue experiments, APC/C substrate specificity assay The EMBO journal High 29150431
2017 BRIT1 is recruited to the Ig heavy chain locus in a γH2AX- and AID-dependent fashion via its C-terminal tandem BRCT domains binding phospho-H2AX; BRIT1 deficiency leads to increased unrepaired Ig breaks and reduced class switch recombination in B cells. Conditional knockout mouse, ChIP, CSR assay, Co-IP, tandem BRCT domain mutant analysis Proceedings of the National Academy of Sciences of the United States of America High 28724724
2018 Both MCPH1 isoforms are phosphorylated by CDK1 during mitosis at several novel sites; upon mitotic exit, both isoforms are degraded by APC/C-CDH1 through distinct degron sequences: the long isoform via a D-box, and the short isoform via a KEN-box. Mass spectrometry phosphorylation mapping, CDK1 inhibitor treatment, APC/C degron mutagenesis, cell-cycle synchronization FASEB journal Medium 30303738
2019 MCPH1 function is dispensable for activation and maintenance of the decatenation checkpoint but is required for the adaptive bypass of the topoisomerase II inhibition-mediated G2 arrest; MCPH1 does not confer adaptation to ATM/ATR-based DNA damage checkpoint. MCPH1-depleted HeLa cells, live-cell imaging of mitotic entry, topoisomerase II inhibitor treatment, checkpoint escape analysis FASEB journal Medium 30964711
2020 MCPH1 is a bona fide DNA-binding protein; it directly interacts with RAD51 at multiple contact points and enhances the stability of RAD51-ssDNA filaments approximately 2-fold as measured by single-molecule tethered particle motion analysis. Purified recombinant protein, DNA-binding assay, Co-immunoprecipitation, single-molecule tethered particle motion analysis Nucleic acids research High 32735676
2020 MCPH1/BRIT1 specifically interacts with the TRFH domain of TRF2 through its 330YRLSP334 motif; TRF2-dependent MCPH1 recruitment promotes DNA repair at dysfunctional telomeres and facilitates telomere replication fork progression and restart of stalled telomere replication forks. Crystal structure of MCPH1-TRF2 complex, Co-immunoprecipitation, telomere FISH, single-molecule DNA fiber analysis Nature communications High 33203878
2020 Loss of MCPH1 causes CDK2-dependent increase in STIL levels at the centrosome, driving centrosome amplification; MCPH1 deep deletions are found in 5–15% of human cancers. TCGA genomic analysis, in cellulo MCPH1 knockdown, STIL centrosome quantification, CDK2 inhibitor rescue Scientific reports Medium 32681070
2021 MCPH1 inhibits condensin II during interphase by binding a short linear motif within MCPH1 to condensin II's NCAPG2 subunit; deletion of Mcph1 in mouse ES cells unleashes condensin II, causing compact chromosomes in G1/G2 even without CDK1 activity and enhancing A/B compartment mixing; fusion of SMC2 with NCAPH2 abrogates MCPH1's inhibitory effect, suggesting a mechanism analogous to WAPL-mediated cohesin regulation. Mouse ES cell Mcph1 deletion, Hi-C chromatin conformation, CDK1 inhibition, SMC2-NCAPH2 fusion rescue experiment, NCAPG2 binding assay eLife High 34850681
2021 The N-terminal BRCT domain of MCPH1 is essential for brain size regulation and gonad development in vivo; Mcph1-ΔBR1 mouse MEFs exhibit PCC phenotype and defective DNA damage response/repair; N-terminal BRCT deletion recapitulates all phenotypes of complete Mcph1 knockout. Mouse model with N-terminal BRCT deletion (Mcph1-ΔBR1), brain size measurement, fertility analysis, MEF PCC assay, DNA damage response assays Cell death & disease High 33542216
2022 MCPH1 central domain (encoded by exon 8) interacts with E3 ligase βTrCP2 and is required for G2/M transition; Mcph1-Δe8 mice show reduced brain size, thinner cortex, sterility, and PCC phenotype in MEFs, demonstrating the central domain's essential role. Mouse model with exon 8 deletion, brain morphology analysis, germ cell analysis, MEF PCC assay, Co-immunoprecipitation Cells High 36078123
2015 MCPH1 maintains epigenetic silencing of ANGPT2 in CLL by binding to the ANGPT2 promoter and recruiting DNA methyltransferases; MCPH1 knockdown results in ANGPT2 upregulation accompanied by loss of promoter methylation. Chromatin immunoprecipitation, co-immunoprecipitation, siRNA knockdown, bisulfite methylation analysis The FEBS journal Medium 25703238
2024 In hematopoietic stem cells, MCPH1 exists in both nuclear and cytoplasmic pools; in the cytoplasm it prevents necroptosis by binding p-RIPK3; aging triggers KAT7-mediated lysine acetylation within the NLS motif of MCPH1, facilitating its nuclear translocation, reducing cytoplasmic MCPH1, and thereby activating necroptosis. HSC fractionation, Co-immunoprecipitation with p-RIPK3, KAT7 acetylation assay, NLS lysine mutant analysis, necroptosis assay Nature aging High 38632351
2024 Mcph1 knockout in mice causes p19ARF upregulation in MEFs leading to cell cycle arrest and cellular senescence; silencing p19Arf restores cell cycle and growth arrest to wild-type levels, placing p19ARF downstream of MCPH1 loss. Mcph1 knockout MEFs, RNA-seq, p19Arf siRNA epistasis, cell cycle and senescence assays International journal of molecular sciences Medium 38731817
2012 MCPH1 represses hTERT transcription by directly binding to the proximal hTERT promoter; overexpression of MCPH1 represses telomerase activity, and MCPH1 knockdown abolishes this repression. EMSA, luciferase promoter assay, siRNA knockdown, telomerase activity assay Gene Medium 22240313

Source papers

Stage 0 corpus · 98 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 MCPH1 regulates the neuroprogenitor division mode by coupling the centrosomal cycle with mitotic entry through the Chk1-Cdc25 pathway. Nature cell biology 195 21947081
2009 BRIT1/MCPH1 links chromatin remodelling to DNA damage response. Nature cell biology 166 19525936
2005 BRIT1/MCPH1 is a DNA damage responsive protein that regulates the Brca1-Chk1 pathway, implicating checkpoint dysfunction in microcephaly. Proceedings of the National Academy of Sciences of the United States of America 144 16217032
1998 Primary autosomal recessive microcephaly (MCPH1) maps to chromosome 8p22-pter. American journal of human genetics 129 9683597
2006 BRIT1 regulates early DNA damage response, chromosomal integrity, and cancer. Cancer cell 121 16872911
2008 Microcephalin/MCPH1 associates with the Condensin II complex to function in homologous recombination repair. The Journal of biological chemistry 93 18718915
2010 BRIT1/MCPH1 is essential for mitotic and meiotic recombination DNA repair and maintaining genomic stability in mice. PLoS genetics 88 20107607
2007 MCPH1 functions in an H2AX-dependent but MDC1-independent pathway in response to DNA damage. The Journal of biological chemistry 88 17925396
2008 MCPH1/BRIT1 cooperates with E2F1 in the activation of checkpoint, DNA repair and apoptosis. EMBO reports 75 18660752
2011 MCPH1 regulates chromosome condensation and shaping as a composite modulator of condensin II. The Journal of cell biology 73 21911480
2007 Distinct BRCT domains in Mcph1/Brit1 mediate ionizing radiation-induced focus formation and centrosomal localization. Oncogene 70 17599047
2006 Misregulated chromosome condensation in MCPH1 primary microcephaly is mediated by condensin II. Cell cycle (Georgetown, Tex.) 66 16434882
2005 SNP array-based homozygosity mapping reveals MCPH1 deletion in family with autosomal recessive mental retardation and mild microcephaly. Human genetics 59 16311745
2013 DNA damage response in microcephaly development of MCPH1 mouse model. DNA repair 55 23683352
2019 Transgenic rhesus monkeys carrying the human MCPH1 gene copies show human-like neoteny of brain development. National science review 49 34691896
2012 Dual recognition of phosphoserine and phosphotyrosine in histone variant H2A.X by DNA damage response protein MCPH1. Proceedings of the National Academy of Sciences of the United States of America 47 22908299
2010 Establishment of a mouse model with misregulated chromosome condensation due to defective Mcph1 function. PloS one 44 20169082
2005 The first missense alteration in the MCPH1 gene causes autosomal recessive microcephaly with an extremely mild cellular and clinical phenotype. Human mutation 44 16211557
2021 MCPH1 inhibits Condensin II during interphase by regulating its SMC2-Kleisin interface. eLife 41 34850681
2015 BRUCE regulates DNA double-strand break response by promoting USP8 deubiquitination of BRIT1. Proceedings of the National Academy of Sciences of the United States of America 39 25733871
2013 Primary microcephaly gene MCPH1 shows signatures of tumor suppressors and is regulated by miR-27a in oral squamous cell carcinoma. PloS one 39 23472065
2020 Cell Metabolic Alterations due to Mcph1 Mutation in Microcephaly. Cell reports 38 32294449
2008 A common SNP of MCPH1 is associated with cranial volume variation in Chinese population. Human molecular genetics 37 18204051
2015 MCPH1: a window into brain development and evolution. Frontiers in cellular neuroscience 36 25870538
2008 Expression analysis of the autosomal recessive primary microcephaly genes MCPH1 (microcephalin) and MCPH5 (ASPM, abnormal spindle-like, microcephaly associated) in human malignant gliomas. Oncology reports 36 18636190
2007 The Drosophila homolog of MCPH1, a human microcephaly gene, is required for genomic stability in the early embryo. Journal of cell science 35 17895362
2013 Mcph1-deficient mice reveal a role for MCPH1 in otitis media. PloS one 33 23516444
2010 Multiple roles of BRIT1/MCPH1 in DNA damage response, DNA repair, and cancer suppression. Yonsei medical journal 33 20376879
2009 Copy number changes of the microcephalin 1 gene (MCPH1) in patients with autism spectrum disorders. Clinical genetics 31 19793310
2011 SET nuclear oncogene associates with microcephalin/MCPH1 and regulates chromosome condensation. The Journal of biological chemistry 29 21515671
2010 MCPH1/BRIT1 limits ionizing radiation-induced centrosome amplification. Oncogene 29 20661222
2016 The DNA damage response molecule MCPH1 in brain development and beyond. Acta biochimica et biophysica Sinica 28 27197793
2011 BRIT1/MCPH1 expression in chronic myeloid leukemia and its regulation of the G2/M checkpoint. Acta haematologica 27 21934293
2014 Emerging roles of MCPH1: expedition from primary microcephaly to cancer. European journal of cell biology 26 24560403
2012 A novel MCPH1 isoform complements the defective chromosome condensation of human MCPH1-deficient cells. PloS one 25 22952573
2013 Combined deletion of two Condensin II system genes (NCAPG2 and MCPH1) in a case of severe microcephaly and mental deficiency. European journal of medical genetics 24 24013099
2017 The E3 ubiquitin ligase APC/CCdh1 degrades MCPH1 after MCPH1-βTrCP2-Cdc25A-mediated mitotic entry to ensure neurogenesis. The EMBO journal 23 29150431
2013 Functional divergence of the brain-size regulating gene MCPH1 during primate evolution and the origin of humans. BMC biology 23 23697381
2011 Molecular basis for the association of microcephalin (MCPH1) protein with the cell division cycle protein 27 (Cdc27) subunit of the anaphase-promoting complex. The Journal of biological chemistry 23 22139841
2006 BRIT1/MCPH1: a guardian of genome and an enemy of tumors. Cell cycle (Georgetown, Tex.) 22 17172830
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2011 VIP blockade leads to microcephaly in mice via disruption of Mcph1-Chk1 signaling. The Journal of clinical investigation 21 21737879
2010 MCPH1 patient cells exhibit delayed release from DNA damage-induced G2/M checkpoint arrest. Cell cycle (Georgetown, Tex.) 21 21150325
2017 MCPH1, mutated in primary microcephaly, is required for efficient chromosome alignment during mitosis. Scientific reports 20 29026105
2016 Targeted Next-Generation Sequencing Identifies a Recurrent Mutation in MCPH1 Associating with Hereditary Breast Cancer Susceptibility. PLoS genetics 20 26820313
2014 Mcph1/Brit1 deficiency promotes genomic instability and tumor formation in a mouse model. Oncogene 20 25362854
2011 Phylogeny and adaptive evolution of the brain-development gene microcephalin (MCPH1) in cetaceans. BMC evolutionary biology 19 21492470
2012 MCPH1/BRIT1 represses transcription of the human telomerase reverse transcriptase gene. Gene 18 22240313
2020 Microcephalin 1/BRIT1-TRF2 interaction promotes telomere replication and repair, linking telomere dysfunction to primary microcephaly. Nature communications 17 33203878
2011 Specific recognition of phosphorylated tail of H2AX by the tandem BRCT domains of MCPH1 revealed by complex structure. Journal of structural biology 17 22154951
2021 The N-terminal BRCT domain determines MCPH1 function in brain development and fertility. Cell death & disease 16 33542216
2012 Two Missense Mutations in the Primary Autosomal Recessive Microcephaly Gene MCPH1 Disrupt the Function of the Highly Conserved N-Terminal BRCT Domain of Microcephalin. Molecular syndromology 15 22855649
2018 Phenotypes in siblings with homozygous mutations of TRAPPC9 and/or MCPH1 support a bifunctional model of MCPH1. Molecular genetics & genomic medicine 14 29693325
2014 The overexpression of MCPH1 inhibits cell growth through regulating cell cycle-related proteins and activating cytochrome c-caspase 3 signaling in cervical cancer. Molecular and cellular biochemistry 14 24633962
2020 Analysis of the "centrosome-ome" identifies MCPH1 deletion as a cause of centrosome amplification in human cancer. Scientific reports 13 32681070
2013 BRIT1 regulates p53 stability and functions as a tumor suppressor in breast cancer. Carcinogenesis 13 23729656
2018 Overexpression of MCPH1 inhibits the migration and invasion of lung cancer cells. OncoTargets and therapy 11 29872322
2015 The UBC Domain Is Required for BRUCE to Promote BRIT1/MCPH1 Function in DSB Signaling and Repair Post Formation of BRUCE-USP8-BRIT1 Complex. PloS one 11 26683461
2015 Overexpression of MCPH1 inhibits uncontrolled cell growth by promoting cell apoptosis and arresting the cell cycle in S and G2/M phase in lung cancer cells. Oncology letters 11 26870219
2012 Identification and functional characterization of a primate-specific E2F1 binding motif regulating MCPH1 expression. The FEBS journal 11 22136275
2009 A pocket on the surface of the N-terminal BRCT domain of Mcph1 is required to prevent abnormal chromosome condensation. Journal of molecular biology 11 19925808
2018 Expression analysis of the MCPH1/BRIT1 and BRCA1 tumor suppressor genes and telomerase splice variants in epithelial ovarian cancer. Gene 10 29860064
2015 Chromosome structure deficiencies in MCPH1 syndrome. Chromosoma 10 25845520
2015 A case report: Autosomal recessive microcephaly caused by a novel mutation in MCPH1 gene. Gene 10 26192461
2014 The Drosophila MCPH1-B isoform is a substrate of the APCCdh1 E3 ubiquitin ligase complex. Biology open 10 24972868
2018 Novel compound heterozygous mutations in MCPH1 gene causes primary microcephaly in Saudi family. Neurosciences (Riyadh, Saudi Arabia) 9 30351297
2014 Primary microcephaly gene MCPH1 shows a novel molecular biomarker of human renal carcinoma and is regulated by miR-27a. International journal of clinical and experimental pathology 9 25197360
2013 MCPH1 deletion in a newborn with severe microcephaly and premature chromosome condensation. European journal of medical genetics 9 24080358
2024 Aging-induced MCPH1 translocation activates necroptosis and impairs hematopoietic stem cell function. Nature aging 8 38632351
2022 Identification of Pathogenic Mutations in Primary Microcephaly- (MCPH-) Related Three Genes CENPJ, CASK, and MCPH1 in Consanguineous Pakistani Families. BioMed research international 8 35281599
2020 Microcephaly family protein MCPH1 stabilizes RAD51 filaments. Nucleic acids research 8 32735676
2023 The emerging role of MCPH1/BRIT1 in carcinogenesis. Frontiers in oncology 7 36845691
2020 Investigation of promoter methylation of MCPH1 gene in circulating cell-free DNA of brain tumor patients. Experimental brain research 7 32556427
2019 MCPH1 is essential for cellular adaptation to the G2-phase decatenation checkpoint. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 7 30964711
2015 MCPH1 maintains long-term epigenetic silencing of ANGPT2 in chronic lymphocytic leukemia. The FEBS journal 7 25703238
2012 A novel mutation in MCPH1 gene in an Iranian family with primary microcephaly. JPMA. The Journal of the Pakistan Medical Association 7 23866422
2022 MCPH1: A Novel Case Report and a Review of the Literature. Genes 6 35456440
2022 Prenatal Identification of a Novel Mutation in the MCPH1 Gene Associated with Autosomal Recessive Primary Microcephaly (MCPH) Using Next Generation Sequencing (NGS): A Case Report and Review of the Literature. Children (Basel, Switzerland) 6 36553323
2014 Phosphorylation of the BRCA1 C terminus (BRCT) repeat inhibitor of hTERT (BRIT1) protein coordinates TopBP1 protein recruitment and amplifies ataxia telangiectasia-mutated and Rad3-related (ATR) Signaling. The Journal of biological chemistry 6 25301947
2022 The Central Domain of MCPH1 Controls Development of the Cerebral Cortex and Gonads in Mice. Cells 5 36078123
2009 The linkage of chromatin remodeling to genome maintenance: contribution from a human disease gene BRIT1/MCPH1. Epigenetics 5 19829069
2020 BRIT1 dysfunction confers synergistic inhibition of hepatocellular carcinoma by targeting poly (ADP-ribose) polymerases and PI3K. American journal of cancer research 4 32642299
2018 Phosphorylation of MCPH1 isoforms during mitosis followed by isoform-specific degradation by APC/C-CDH1. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 4 30303738
2017 BRCT-domain protein BRIT1 influences class switch recombination. Proceedings of the National Academy of Sciences of the United States of America 4 28724724
2020 Primary Microcephaly with Novel Variant of MCPH1 Gene in Twins: Both Manifesting in Childhood at the Same Time with Hashimoto's Thyroiditis. Journal of pediatric genetics 3 32714618
2024 The analyses of human MCPH1 DNA repair machinery and genetic variations. Open medicine (Warsaw, Poland) 2 38463519
2020 Generation of a MCPH1 knockout human embryonic stem cell line by CRISPR/Cas9 technology. Stem cell research 2 33370873
2019 Genetic association and functional characterization of MCPH1 gene variation in bipolar disorder and schizophrenia. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2 30859703
2018 Silencing BRIT1 Facilitates the Abilities of Invasiveness and Migration in Trophoblast Cells. Medical science monitor : international medical journal of experimental and clinical research 2 30337515
2017 CMA analysis identifies homozygous deletion of MCPH1 in 2 brothers with primary Microcephaly-1. Molecular cytogenetics 2 28878824
2009 The c.940G variant of the Microcephalin (MCPH1) gene is not associated with microcephaly or mental retardation. American journal of medical genetics. Part A 2 19267414
2024 Microcephaly Gene Mcph1 Deficiency Induces p19ARF-Dependent Cell Cycle Arrest and Senescence. International journal of molecular sciences 1 38731817
2024 Functional analysis of a novel intronic variant of MCPH1 with autosomal recessive primary microcephaly. Heliyon 1 38818167
2020 MCPH1 Lack of Function Enhances Mitotic Cell Sensitivity Caused by Catalytic Inhibitors of Topo II. Genes 1 32276518
2026 Differential sensitivity of MCPH1- and BRCA2-deficient cancer cells to PARP-1 inhibition. PloS one 0 41931484
2024 Mcph1, mutated in primary microcephaly, is also crucial for erythropoiesis. EMBO reports 0 38605277
2024 Generation and analysis of mouse embryonic stem cells with knockout of the Mcph1 (microcephalin) gene. Vavilovskii zhurnal genetiki i selektsii 0 39280843
2016 The Impact of rs3762271 and rs930557 Polymorphisms of ASPM and MCPH1 Genes on the Anatomy and Function of the Brain. Biological research for nursing 0 26912502