Affinage

POLL

DNA polymerase lambda · UniProt Q9UGP5

Length
575 aa
Mass
63.5 kDa
Annotated
2026-06-14
40 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DNA polymerase lambda (POLL) is a family X DNA repair polymerase that fills short DNA gaps during base excision repair (BER) and non-homologous end joining (NHEJ), using a two-metal-ion phosphoryl transfer mechanism in which Mn2+/Mg2+ at the metal A site positions the primer 3'-OH in-line with the alpha-phosphate for catalysis (PMID:17475573). It is template-dependent, lacks proofreading, is processive on small 5'-phosphate-containing gaps, and has high dNTP affinity consistent with function at low cellular dNTP levels (PMID:11821417). Pol lambda serves as a backup to Pol beta in BER, substituting for it in cell-extract repair (PMID:15749700), and it cooperates with the MUTYH glycosylase, PCNA, FEN1, and DNA ligases in a reconstituted pathway that repairs A:8-oxo-G mispairs (PMID:19820168). Its medium fidelity is mechanistically enforced by a closed apo-conformation with a preformed MgdNTP pocket whose hydrophobic core attenuates MgdNTP prebinding (PMID:26836966) and by Loop 1, which controls dNTP-induced template-strand and primer-terminus movements (PMID:20435673); structural studies further show it accommodates 8-oxo-dG in anti and syn forms and discriminates against the mutagenic pairing at the extension step (PMID:27481934). In NHEJ, Pol lambda extends mismatched and partially paired ends (PMID:16807316), is stimulated and recruited to damage by the XRCC4 paralogs PAXX, XLF, and XRCC4 binding its SP/8 kDa domain (PMID:30250067), and its catalytic activity is relieved from an autoinhibitory BRCT–catalytic domain interaction by Ku binding within the short-range synaptic complex (PMID:41700088). Its non-catalytic BRCT and proline-rich N-terminal domains suppress polymerase activity and DNA/partner interactions, govern nuclear localization and chromatin recruitment, and confer selective tolerance of oxidative damage (PMID:28380295, PMID:38093124). Pol lambda activity is post-translationally tuned by CDK2 phosphorylation of Thr553, which protects it from ubiquitin-proteasomal degradation across the cell cycle (PMID:18688254), and by RanBP2-mediated SUMOylation at Lys27, which promotes nuclear entry and damage recruitment (PMID:32224012).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2000 Medium

    Established that POLL encodes an intrinsically active DNA polymerase of the family X repair class, distinguished from Pol beta by an additional BRCT domain.

    Evidence In situ gel polymerase activity assay of murine Pol lambda overexpressed in E. coli with sequence analysis

    PMID:10966791

    Open questions at the time
    • Activity shown only in an overexpression system
    • No defined repair substrate or cellular pathway assigned
    • dRPase activity inferred from conserved residues, not measured
  2. 2002 High

    Defined the enzymatic profile pointing to BER: template-dependent, processive on 5'-phosphate gaps, no proofreading, and high dNTP affinity, while identifying PCNA as a negative regulator acting through the proline-rich suppressor domain.

    Evidence Biochemical assays with purified recombinant human Pol lambda; truncation mutants and in vitro PCNA interaction; calf-thymus native protein characterization

    PMID:11821417 PMID:11886860 PMID:12081642

    Open questions at the time
    • BER role inferred from biochemistry, not yet genetically demonstrated
    • Physiological relevance of PCNA suppression untested in cells
    • Damaged-template preference not mechanistically explained
  3. 2004 High

    Provided the structural basis for gap-filling, showing limited template contacts and a DNA shift resembling a deletion intermediate, foreshadowing frameshift propensity.

    Evidence 2.1 Å crystal structure of the catalytic core on two-nucleotide gap DNA, compared to Pol beta

    PMID:14992725

    Open questions at the time
    • Catalytic chemistry not yet captured
    • Role of N-terminal domains not addressed by core structure
    • Functional consequence of deletion-like intermediate not tested
  4. 2005 High

    Demonstrated genetically that Pol lambda substitutes for Pol beta in BER and mapped a non-canonical PCNA-binding region controlling distributive activity.

    Evidence Cell-extract BER assays in pol beta-/- and pol lambda-/- MEFs with neutralizing antibodies; reciprocal pulldown, co-IP, and EGFP co-localization for PCNA

    PMID:15749700 PMID:15966901

    Open questions at the time
    • Relative in vivo contribution of Pol lambda vs Pol beta unquantified
    • Conditions selecting Pol lambda over Pol beta unclear
    • PCNA recruitment dynamics at lesions not defined
  5. 2007 High

    Resolved the two-metal-ion catalytic mechanism and connected Pol lambda to oxidative-damage processing by showing non-mutagenic extension of 8-oxoG:dCMP.

    Evidence 1.9/2.0 Å crystal structures with catalysis observed upon MnCl2 soaking; primer-extension kinetics on 8-oxoG and m6G templates

    PMID:17475573 PMID:17686665

    Open questions at the time
    • Structural basis of syn/anti 8-oxoG discrimination not yet resolved
    • In vivo relevance of damage-tolerant extension untested
    • Metal selectivity (Mn vs Mg) physiology unaddressed
  6. 2008 High

    Identified cell-cycle-coupled stability control, showing CDK2 phosphorylation of Thr553 protects Pol lambda from ubiquitin-proteasomal degradation, and partner-mediated TLS stimulation by RPA.

    Evidence In vitro CDK2 kinase assay, phospho-defective mutant, cell-cycle synchronization and proteasome inhibition; in vitro TLS reconstitution with RPA domain-deletion mutants

    PMID:18688254 PMID:18976222

    Open questions at the time
    • E3 ligase targeting Pol lambda not identified
    • Functional output of S/G2 stabilization not linked to a repair event
    • RPA stimulation mechanism not structurally defined
  7. 2009 High

    Placed Pol lambda within a complete reconstituted pathway for repair of A:8-oxo-G mispairs, defining its functional partners in oxidative-damage repair.

    Evidence Immunofluorescence in ROS-exposed cells, DNA pulldown from extracts, and full reconstitution with purified MUTYH, Pol lambda, FEN1, and DNA ligase I

    PMID:19820168

    Open questions at the time
    • Order and regulation of factor handoff not defined
    • Direct Pol lambda–MUTYH interaction surface unmapped
    • Contribution relative to other polymerases in vivo unquantified
  8. 2010 High

    Defined structural determinants of fidelity (Loop 1 controlling template/primer movement) and the active-site recognition of nucleoside-analog drugs.

    Evidence Crystal structures of loop 1 mutant with NHEJ and fidelity assays; structures of AraC/gemcitabine bound in the nascent base-pair pocket with kinetics

    PMID:20348107 PMID:20435673

    Open questions at the time
    • Loop 1 contribution to in vivo mutagenesis not measured
    • Therapeutic relevance of analog incorporation untested in cells
    • Interplay of Loop 1 with N-terminal domains unaddressed
  9. 2013 High

    Established a mechanism of irreversible lyase-driven self-inactivation by oxidized abasic lesions through covalent modification of active-site lysines.

    Evidence Single-turnover kinetics and mass spectrometry of GluC-digested inactivated Pol lambda with defined DOB/pC4-AP substrates

    PMID:23330920

    Open questions at the time
    • Cellular consequences of this suicide inactivation not demonstrated
    • Whether inactivation occurs at physiological lesion levels unknown
    • Relationship to Pol beta inactivation in shared lesions not resolved
  10. 2014 Medium

    Assigned functions to the non-catalytic N-terminal domains, showing BRCT and proline-rich regions drive homology-mediated primer realignment and frameshift mutagenesis.

    Evidence Primer extension and HT-SOSA sequencing with N-terminal deletion constructs on abasic and 8-oxodG substrates

    PMID:25108835

    Open questions at the time
    • In vivo frameshift signature not established
    • Structural basis of realignment by N-terminal domains unresolved
    • Single-lab biochemical observation
  11. 2016 High

    Provided a unified structural-kinetic model of medium fidelity, defining 8-oxoG handling at the extension step and a hydrophobic core that attenuates MgdNTP prebinding.

    Evidence Multiple crystal structures (7 and 12) with pre-steady-state kinetics and mutagenesis (L431A, kinetic-switch residue)

    PMID:26836966 PMID:27481934

    Open questions at the time
    • Cellular fidelity consequences of core mutations untested
    • Long-patch vs short-patch BER routing in vivo unconfirmed
    • Generalizability of prebinding model to all substrates unclear
  12. 2017 Medium

    Showed that the BRCT and proline/serine-rich domains restrain nuclear import and govern damage-induced chromatin recruitment, conferring selective tolerance of oxidative damage.

    Evidence Fluorescence microscopy, fractionation, and survival assays with BRCT/PSR/NLS deletion constructs

    PMID:28380295

    Open questions at the time
    • Molecular signal triggering recruitment unidentified
    • Mechanism distinguishing oxidative vs methylation tolerance unclear
    • Single-lab cell-based study
  13. 2018 High

    Identified the XRCC4-paralog interface, showing PAXX, XLF, and XRCC4 bind the SP/8 kDa domain to stimulate activity and recruit Pol lambda to DSBs for joining of incompatible ends.

    Evidence Interactome, direct binding, activity stimulation, laser micro-irradiation recruitment, and in vivo NHEJ assays across three paralogs

    PMID:30250067

    Open questions at the time
    • Structural detail of the SP/8 kDa–head domain interface not solved
    • Hierarchy among the three paralogs in vivo not fully resolved
    • Integration with core NHEJ machinery timing unclear
  14. 2020 High

    Defined a SUMO-dependent nuclear import route, with RanBP2 SUMOylating Lys27 at the nuclear pore to enable damage recruitment.

    Evidence In vitro and in vivo SUMOylation, K27 mutagenesis, nuclear fractionation, and damage-recruitment imaging

    PMID:32224012

    Open questions at the time
    • Interplay between SUMOylation and BRCT/PSR import restraint unresolved
    • Whether SUMOylation is damage-inducible at the modification step unclear
    • deSUMOylation/reversal not characterized
  15. 2021 Medium

    Extended Pol lambda's repertoire to error-free TLS of 1-MeA and to telomere maintenance, including a role in ALT activity.

    Evidence Biochemical TLS with epistasis to Pol zeta in human cells; annealing/extension assays with POT1/TPP1, TERRA, RPA regulation and telomere co-localization/knockdown

    PMID:33673424 PMID:34119520

    Open questions at the time
    • In vivo significance of telomeric role beyond ALT cells unknown
    • Structural basis of 1-MeA Hoogsteen bypass not solved
    • Single-lab observations for each role
  16. 2024 Medium

    Showed that microenvironment and Loop 1 sequence tune Pol lambda's end-joining behavior: XRCC1 microphase separation stimulates gap filling, and a Loop 1 variant gains Pol mu-like unpaired-primer synthesis.

    Evidence In vitro gap-filling with DLS and microscopy of XRCC1 microphases; NHEJ and paired/unpaired primer-extension assays with the PolλKGET Loop 1 variant

    PMID:38428373 PMID:39000034

    Open questions at the time
    • Physiological occurrence of microphase separation unverified
    • How Loop 1 confers activity without DNA contact unexplained
    • In vivo relevance of engineered Loop 1 variant unknown
  17. 2026 High

    Resolved the principal autoregulatory switch, demonstrating an intramolecular BRCT–catalytic autoinhibition relieved by Ku binding to activate Pol lambda within the NHEJ synaptic complex.

    Evidence Structural prediction with biochemical activity and single-molecule assays and KBM mutagenesis

    PMID:41700088

    Open questions at the time
    • High-resolution structure of the autoinhibited state not determined
    • Coordination of Ku relief with XRCC4-paralog and PTM regulation unresolved
    • Whether the same switch operates in BER unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple regulatory layers—N-terminal autoinhibition, Ku/XRCC4-paralog stimulation, PCNA/RPA/PARP1/XRCC1 modulation, and CDK2/SUMO post-translational control—are integrated to select Pol lambda for BER versus NHEJ versus telomere maintenance in vivo remains unresolved.
  • No unified in vivo model coordinating the regulatory inputs
  • Quantitative pathway partitioning of Pol lambda not established
  • No disease association mapped within the available corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140097 catalytic activity, acting on DNA 4 GO:0003677 DNA binding 3 GO:0016740 transferase activity 3 GO:0016787 hydrolase activity 2
Localization
GO:0005634 nucleus 3 GO:0005694 chromosome 1
Pathway
R-HSA-73894 DNA Repair 4
Partners
KUMUTYHPAXXPCNARPAXLFXRCC1XRCC4
Complex memberships
NHEJ short-range synaptic complex

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 Murine Pol lambda (POLL) displays intrinsic DNA polymerase activity when overproduced in E. coli, assessed by in situ gel analysis. It contains all critical residues for DNA binding, nucleotide binding, selection, and catalysis conserved in family X polymerases, including residues required for deoxyribose phosphate lyase (dRPase) activity. Its BRCT domain (first 230 aa) has no counterpart in Pol beta. In situ gel DNA polymerase activity assay; sequence analysis; Northern blotting and immunostaining for localization Journal of molecular biology Medium 10966791
2002 Human Pol lambda inserts nucleotides in a template-dependent manner and is processive on small gaps containing a 5'-phosphate group. It lacks proofreading activity and has ~37-fold higher affinity for dNTPs than Pol beta, consistent with function under low cellular dNTP levels. These properties support a role in base excision repair. Purification of recombinant human Pol lambda; biochemical polymerization and fidelity assays; nucleotide insertion kinetics The Journal of biological chemistry High 11821417
2002 Pol lambda has intrinsic template-directed DNA polymerase activity requiring Mn2+ or Mg2+ as metal cofactors. The proline-rich region acts as a suppressor domain for its polymerization activity (SDPA). PCNA directly interacts with Pol lambda through its Pol beta-like region in vitro, and this interaction negatively regulates Pol lambda activity. Recombinant protein expression in E. coli; truncation mutants; chimeric enzyme construction; in vitro PCNA interaction assay Genes to cells Medium 12081642
2002 Calf thymus-purified Pol lambda preferentially replicates damaged DNA and is aphidicolin-sensitive (unlike Pol beta). It has no detectable nuclease activity and is 6-fold more accurate than Pol beta in an M13mp2 forward mutation assay. Protein purification from calf thymus (5 chromatographic steps); polymerase activity assay on damaged and undamaged DNA; M13mp2 forward mutation assay The Journal of biological chemistry Medium 11886860
2004 Crystal structure of human Pol lambda catalytic core in complex with a two-nucleotide gap DNA at 2.1 Å reveals limited contacts with template strand at the active site, a shift in DNA position reminiscent of a deletion intermediate, and the ability to adopt a closed conformation even without dNTP binding. X-ray crystallography (2.1 Å resolution); structural comparison with Pol beta ternary complex Molecular cell High 14992725
2005 Pol lambda contributes to base excision repair (BER) as a backup to Pol beta. Using extracts from pol beta-/- and pol lambda-/- mouse embryonic fibroblasts combined with neutralizing antibodies, pol lambda antibody strongly reduced in vitro BER in pol beta-/- extracts, demonstrating pol lambda can substitute for pol beta in BER. Cell extract BER assay; pol lambda-/- and pol beta-/- mouse embryonic fibroblasts; neutralizing antibodies against pol lambda and pol beta The Journal of biological chemistry High 15749700
2005 Pol lambda directly binds PCNA through a confined C-terminal region (residues 518–537), distinct from the canonical PIM motif. In vivo, Pol lambda co-immunoprecipitates with PCNA and EGFP-tagged Pol lambda co-localizes with PCNA as nuclear spots. PCNA binding suppresses the distributive nucleotidyltransferase activity of Pol lambda. Pull-down assay with deletion mutants; competitive peptide assay; co-immunoprecipitation; fluorescence microscopy (EGFP co-localization) Genes to cells High 15966901
2006 Pol lambda extends mismatched primer termini with ~10^-2 efficiency relative to matched pairs; efficiency is ~260-fold higher on 1-nt gapped molecules with 5'-phosphate versus open template-primer. A 2.4 Å crystal structure of Pol lambda with a dG:dGMP mismatch at the primer terminus shows Pol lambda cannot distinguish matched from mismatched termini during DNA binding, explaining its mismatch extension capacity relevant to NHEJ. In vitro mismatch extension kinetics; X-ray crystallography (2.4 Å) of mismatch-containing complex Nucleic acids research High 16807316
2007 Crystal structures of Pol lambda at 1.9 Å (with non-hydrolyzable dUpnpp and Na+ at metal A site) and 2.0 Å (after soaking in MnCl2) reveal that Mn2+ occupying the metal A site induces a C3'-endo ribose conformation that positions the 3'-OH in-line with the alpha-phosphate, supporting a two-metal-ion catalytic mechanism. Catalysis in the crystal was directly observed upon MnCl2 soaking. X-ray crystallography (1.9 Å and 2.0 Å structures); crystal soaking experiments; structural comparison of pre- and post-catalytic states DNA repair High 17475573
2007 Pol lambda efficiently uses 8-oxoguanine (8-oxoG) as a template, inserting either dAMP or dCMP opposite it, but strongly discriminates against extension of the mutagenic 8-oxoG:dAMP pair while readily extending the non-mutagenic 8-oxoG:dCMP pair. Similar non-mutagenic extension was shown for O6-methylguanine. In vitro primer extension assay; kinetic analysis with purified human Pol lambda on 8-oxoG and m6G templates DNA repair Medium 17686665
2008 CDK2 phosphorylates Pol lambda in vitro. Phosphorylation of Thr553 is important for Pol lambda stability; a phosphorylation-defective T553 mutant is targeted for proteasomal degradation via ubiquitination. Pol lambda is stabilized during late S and G2 phases of the cell cycle, mimicking CDK2/cyclin A activity. In vitro kinase assay (CDK2); phosphorylation-defective mutant analysis; cell cycle synchronization; proteasome inhibitor experiments; Western blotting EMBO reports High 18688254
2008 RPA stimulates translesion DNA synthesis by Pol lambda in its globular conformation (not extended). This stimulation requires the p70N and p32C domains of RPA for protein-protein interactions. In vitro TLS assay with purified Pol lambda, RPA, and mutant hABCD RPA lacking protein-protein interaction domains; primer-template substrates with 8-oxoguanine Biochemistry. Biokhimiia Medium 18976222
2009 MUTYH glycosylase and Pol lambda cooperate in a complete 8-oxo-G repair pathway. MUTYH, Pol lambda, PCNA, FEN1, and DNA ligases I and III are specifically recruited from human cell extracts to A:8-oxo-G DNA. The full repair pathway for A:8-oxo-G mispairs was reconstituted in vitro with purified MUTYH, Pol lambda, FEN1, and DNA ligase I. Immunofluorescence in ROS-exposed cells; in vitro DNA pulldown from cell extracts; full pathway reconstitution with purified proteins Proceedings of the National Academy of Sciences of the United States of America High 19820168
2010 Loop 1 of Pol lambda modulates fidelity by controlling dNTP-induced movements of the template strand and primer-terminal 3'-OH during the inactive-to-active conformation transition. Replacing 9 loop 1 residues with those from Pol beta did not affect catalytic efficiency for correct incorporation or NHEJ participation but significantly reduced accuracy in three biochemical fidelity assays. X-ray crystallography of loop 1 mutant (binary and ternary complexes); in vitro NHEJ assay; multiple fidelity assays; structural comparison Nucleic acids research High 20435673
2010 Crystal structures show AraC and gemcitabine (dFdC) can bind within the nascent base pair binding pocket of Pol lambda. Pol lambda efficiently incorporates AraCTP but not dFdCTP, with the conformation of dFdCTP ribose being significantly different from normal dCTP. X-ray crystallography of Pol lambda bound to AraC or dFdC opposite template dG in gapped DNA; kinetic incorporation assays The Journal of biological chemistry High 20348107
2011 Pol lambda undergoes ubiquitylation as a post-translational modification that regulates its stability and possibly subcellular localization during the cell cycle. Review summarizing experimental evidence for Pol lambda ubiquitylation (referenced from primary experiments) FEBS letters Low 21486570
2012 Pol lambda can perform gap-filling BER bypass of AP sites located at positions adjacent to (+)-cis-BPDE-dG adducts (but not trans-isomers), inserting correct dCTP. AP sites directly opposite cis-BP adducts can be repaired by Pol lambda but not Pol beta. In vitro primer extension and gap-filling assays with defined AP-site-containing oligonucleotide substrates bearing cis- or trans-BPDE-dG adducts; comparison of Pol lambda vs Pol beta DNA repair Medium 22317757
2013 Pol lambda is irreversibly inactivated by oxidized abasic lesions DOB and pC4-AP via covalent modification of active-site Lys324 (and potentially Lys312) in its lyase active site. Lyase inactivation also prevents polymerization. DOB inactivates Pol lambda ~3-fold less efficiently than Pol beta. Single-turnover kinetics; mass spectrometry of GluC-digested inactivated Pol lambda; defined lesion-containing DNA substrates Biochemistry High 23330920
2014 The BRCT domain of Pol lambda enhances abasic site bypass efficiency (~1.6-fold). The BRCT and proline-rich domains cooperatively promote -2 frameshift mutations through homology-driven primer realignment and increase -1 frameshift frequency during 8-oxodG bypass. Primer extension assays; high-throughput short oligonucleotide sequencing assay (HT-SOSA); N-terminal deletion constructs of Pol lambda DNA repair Medium 25108835
2016 Seven crystal structures and pre-steady-state kinetics characterize 8-oxo-dG bypass by Pol lambda. Pol lambda accommodates 8-oxo-dG in both anti and syn conformations; discrimination against the pro-mutagenic syn-conformation occurs at the extension step. A specific residue acts as a kinetic switch shunting repair toward long-patch BER upon correct dCMP insertion. X-ray crystallography (7 novel structures); pre-steady-state kinetics; mutagenesis to identify fidelity-determining residue The EMBO journal High 27481934
2016 Pol lambda apo-form exists in a closed conformation with a preformed MgdNTP binding pocket; a hydrophobic core (Leu431, Ile492, Tyr505/Phe506) attenuates MgdNTP prebinding to maintain medium fidelity. L431A mutation enhances MgdNTP prebinding and lowers fidelity. MgdNTP prebinding can stabilize mismatched and destabilize matched ternary complexes. X-ray crystallography (12 crystal structures); pre-steady-state kinetics; site-directed mutagenesis (L431A) Journal of the American Chemical Society High 26836966
2017 The BRCT and proline/serine-rich (PSR) domains of Pol lambda impede its nuclear localization; the nuclear localization signal (NLS) is required to overcome this impediment. DNA damage induces Pol lambda recruitment to chromatin, controlled by the BRCT and PSR domains. Both domains are required for Pol lambda-mediated tolerance of oxidative but not methylation DNA damage. Western blot; fluorescence microscopy; cell survival assays; deletion constructs of BRCT, PSR, and NLS domains Chemical research in toxicology Medium 28380295
2018 PAXX, XLF, and XRCC4 share the ability to interact with Pol lambda, stimulate its activity, and are required for recruitment of Pol lambda to laser-induced DNA damage sites. Stimulation requires direct interaction between the SP/8 kDa domain of Pol lambda and the N-terminal head domains of XRCC4 paralogs to facilitate recognition of 5' end of substrate gaps. PAXX and XLF collaborate with Pol lambda for joining of incompatible DNA ends and are redundant in supporting Pol lambda function in vivo. Interactome analysis; direct interaction assays; Pol lambda activity stimulation assays; laser micro-irradiation and recruitment assays; in vivo NHEJ assay Nature communications High 30250067
2020 Pol lambda is SUMOylated in vitro and in vivo, with Lys27 being the primary SUMO conjugation site. SUMOylation is mediated by the E3 ligase RanBP2 at the nuclear pore complex. This modification promotes Pol lambda nuclear entry, which is required for its recruitment to DNA lesions and is stimulated by DNA damage. In vitro SUMOylation assay; in vivo SUMOylation (co-IP); site-directed mutagenesis (K27); nuclear fractionation; immunofluorescence and damage recruitment assays Journal of molecular biology High 32224012
2021 Pol lambda promotes error-free replication through N1-methyl-deoxyadenosine (1-MeA) by inserting the correct nucleotide T opposite 1-MeA, likely via Hoogsteen base pairing with 1-MeA in a syn conformation. Pol lambda acts as the insertion polymerase in a Pol lambda/Pol zeta-dependent TLS pathway for 1-MeA bypass. Biochemical TLS assay with purified Pol lambda; genetic analysis in human cells (siRNA knockdown); epistasis with Pol zeta The Journal of biological chemistry Medium 34119520
2021 Pol lambda promotes annealing of G-rich telomeric repeats to complementary strands and can prime DNA synthesis on these substrates. POT1/TPP1 heterodimer stimulates this activity, while TERRA RNA and RPA negatively regulate it. Pol lambda associates with telomeres and co-localizes with TPP1 in cells, and its silencing represses ALT activity and induces telomeric stress. Annealing and primer extension assays with purified proteins; co-immunoprecipitation/ChIP for telomere association; immunofluorescence co-localization; siRNA knockdown with ALT activity readout International journal of molecular sciences Medium 33673424
2023 The non-catalytic N-terminal region of Pol lambda (BRCT and proline-rich domains) suppresses both its polymerase activity and its interactions with DNA and with PARP1. RPA interaction with Pol lambda is also modulated by these non-catalytic domains. In vitro polymerase activity assays; protein-protein interaction assays (Pol lambda with PARP1 and RPA); N-terminal deletion constructs Doklady. Biochemistry and biophysics Low 38093124
2024 A Pol lambda loop 1 variant (PolλKGET) retains canonical Pol lambda activity on paired DNA ends but acquires the ability to synthesize from unpaired primer termini—activity normally unique to Pol mu. The Loop1 amino acid sequence is essential for this gained activity during NHEJ despite making no direct contact with DNA substrate. In vitro NHEJ assay; primer extension on paired and unpaired substrates; structural prediction DNA repair Medium 38428373
2024 XRCC1 stimulates the gap-filling activity of Pol lambda under conditions of microphase separation. XRCC1 forms protein-rich microphases with DNA, and Pol lambda, XRCC1, and gapped DNA co-localize within these microphases. Stimulation occurs at micromolar XRCC1 concentrations and requires both protein-protein interaction and microphase separation conditions. In vitro gap-filling assay; dynamic light scattering; fluorescence microscopy for co-localization in microphases; binding affinity measurement for XRCC1-Pol lambda complex International journal of molecular sciences Medium 39000034
2026 Pol lambda possesses an autoinhibitory intramolecular interaction between its N-terminal BRCT domain and C-terminal catalytic domain. Ku binding to the KBM within the BRCT domain relieves this autoinhibition, increasing both Pol lambda binding rate to primer-template DNA and nucleotide incorporation rate. Single-molecule assays demonstrate Ku stimulates Pol lambda polymerase activity at DSBs within the short-range synaptic complex during NHEJ. Structural prediction; biochemical activity assays; single-molecule approaches; KBM mutagenesis Nucleic acids research High 41700088

Source papers

Stage 0 corpus · 40 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 DNA polymerase lambda (Pol lambda), a novel eukaryotic DNA polymerase with a potential role in meiosis. Journal of molecular biology 239 10966791
2002 DNA polymerase lambda, a novel DNA repair enzyme in human cells. The Journal of biological chemistry 169 11821417
2005 DNA polymerase lambda mediates a back-up base excision repair activity in extracts of mouse embryonic fibroblasts. The Journal of biological chemistry 132 15749700
2004 A structural solution for the DNA polymerase lambda-dependent repair of DNA gaps with minimal homology. Molecular cell 118 14992725
2002 Over-expression of human DNA polymerase lambda in E. coli and characterization of the recombinant enzyme. Genes to cells : devoted to molecular & cellular mechanisms 104 12081642
2009 An 8-oxo-guanine repair pathway coordinated by MUTYH glycosylase and DNA polymerase lambda. Proceedings of the National Academy of Sciences of the United States of America 103 19820168
2002 DNA polymerase lambda from calf thymus preferentially replicates damaged DNA. The Journal of biological chemistry 63 11886860
2007 Role of the catalytic metal during polymerization by DNA polymerase lambda. DNA repair 60 17475573
2014 Structure-function studies of DNA polymerase λ. Biochemistry 57 24716527
2005 Structure-function studies of DNA polymerase lambda. DNA repair 56 16213194
2006 Promiscuous mismatch extension by human DNA polymerase lambda. Nucleic acids research 39 16807316
2002 Petasiphenol: a DNA polymerase lambda inhibitor. Biochemistry 38 12463744
2008 Control of DNA polymerase lambda stability by phosphorylation and ubiquitination during the cell cycle. EMBO reports 35 18688254
2007 Human DNA polymerase lambda is a proficient extender of primer ends paired to 7,8-dihydro-8-oxoguanine. DNA repair 34 17686665
2010 Loop 1 modulates the fidelity of DNA polymerase lambda. Nucleic acids research 33 20435673
2016 A fidelity mechanism in DNA polymerase lambda promotes error-free bypass of 8-oxo-dG. The EMBO journal 30 27481934
2005 Inhibitory effect of tocotrienol on eukaryotic DNA polymerase lambda and angiogenesis. Biochemical and biophysical research communications 30 16325764
2018 PAXX and its paralogs synergistically direct DNA polymerase λ activity in DNA repair. Nature communications 26 30250067
2005 DNA polymerase lambda directly binds to proliferating cell nuclear antigen through its confined C-terminal region. Genes to cells : devoted to molecular & cellular mechanisms 25 15966901
2013 Expanding the scope of human DNA polymerase λ and β inhibitors. ACS chemical biology 22 24171552
2013 DNA polymerase λ inactivation by oxidized abasic sites. Biochemistry 19 23330920
2012 Human DNA polymerase λ catalyzes lesion bypass across benzo[a]pyrene-derived DNA adduct during base excision repair. DNA repair 18 22317757
2010 Interaction between DNA Polymerase lambda and anticancer nucleoside analogs. The Journal of biological chemistry 18 20348107
2017 Living on the Edge: DNA Polymerase Lambda between Genome Stability and Mutagenesis. Chemical research in toxicology 14 28841305
2011 Ubiquitylation of DNA polymerase λ. FEBS letters 13 21486570
2018 Mutations induced by 8-oxo-7,8-dihydroguanine in WRN- and DNA polymerase λ-double knockdown cells. Mutagenesis 11 30137433
2020 RanBP2-Mediated SUMOylation Promotes Human DNA Polymerase Lambda Nuclear Localization and DNA Repair. Journal of molecular biology 10 32224012
2016 Structural Mechanism for the Fidelity Modulation of DNA Polymerase λ. Journal of the American Chemical Society 10 26836966
2008 Interaction between DNA Polymerase lambda and RPA during translesion synthesis. Biochemistry. Biokhimiia 8 18976222
2024 The enzymatic properties of Arabidopsis thaliana DNA polymerase λ suggest a role in base excision repair. Plant molecular biology 6 38217735
2021 DNA polymerase λ promotes error-free replication through Watson-Crick impairing N1-methyl-deoxyadenosine adduct in conjunction with DNA polymerase ζ. The Journal of biological chemistry 6 34119520
2017 Noncatalytic, N-terminal Domains of DNA Polymerase Lambda Affect Its Cellular Localization and DNA Damage Response. Chemical research in toxicology 6 28380295
2014 N-terminal domains of human DNA polymerase lambda promote primer realignment during translesion DNA synthesis. DNA repair 5 25108835
2021 A Role for Human DNA Polymerase λ in Alternative Lengthening of Telomeres. International journal of molecular sciences 3 33673424
2024 DNA polymerase λ Loop1 variant yields unexpected gain-of-function capabilities in nonhomologous end-joining. DNA repair 2 38428373
2024 DNA Repair Protein XRCC1 Stimulates Activity of DNA Polymerase λ under Conditions of Microphase Separation. International journal of molecular sciences 2 39000034
2026 DNA repair under heat: DNA polymerase λ modulates heat stress-induced mutagenesis in plants. The Plant cell 1 41875383
2023 Non-Catalytic Domains of DNA Polymerase λ: Influence on Enzyme Activity and Its Regulation. Doklady. Biochemistry and biophysics 1 38093124
2014 Inhibition of DNA polymerase λ and associated inflammatory activities of extracts from steamed germinated soybeans. Food & function 1 24519361
2026 DNA polymerase λ autoinhibition is relieved via Ku interaction during non-homologous end joining. Nucleic acids research 0 41700088

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