RPL6

RPL6 (eL6/TAXREB107) is a 60S large ribosomal subunit protein that, beyond its core role in translation, carries out a range of extraribosomal regulatory functions in transcription, the DNA damage response, the cell cycle, and oncogenic signaling (PMID:8457378, PMID:30598506). It was first identified as a sequence-specific DNA-binding protein recognizing domain C of the HTLV-1 Tax-responsive enhancer and as a direct interactor of the Tax transactivator and of intracellular FGF-2, positioning it within virus-induced and growth-factor transcriptional cross-talk (PMID:8457378, PMID:9826564, PMID:12007002). In the DNA damage response, RPL6 binds histone H2A and is recruited to damage sites in a PARP-dependent manner, where it promotes the MDC1–γH2AX interaction and the downstream RNF168/H2AK15ub/53BP1/BRCA1 cascade and the G2-M checkpoint (PMID:30598506); consistent with this PARP linkage, ribosome-free RPL6 is a major HPF1-dependent substrate of PARP1/PARP2 ADP-ribosylation in vitro [PMID:bio_10.1101_2025.09.15.676193]. RPL6 also supports cell-cycle G1/S progression by maintaining cyclin E expression (PMID:22043320), and stabilizes HMGCS1 mRNA through 3'UTR binding to elevate cholesterol and thereby HIF-1α signaling (PMID:40650669). Its abundance is controlled post-translationally: UBE2T conjugates K48-linked polyubiquitin to RPL6 to drive proteasomal degradation, which modulates wild-type and mutant p53 activity (PMID:36156329). Through direct partners NSUN2, EIF2B5, CacyBP/SIP, and cGAS, RPL6 is further coupled to RNA methylation, PI3K/AKT/mTOR signaling, nascent protein synthesis, and cGAS-STING innate immune signaling (PMID:31487418, PMID:40246131, PMID:40691326, PMID:41318619).

1. 1993 Medium

   Established that RPL6 has a sequence-specific DNA-binding activity at the HTLV-1 enhancer, the first hint of an extraribosomal transcriptional role.

   Evidence Yeast fusion-protein DNA-binding assay and Northern/immunoblot in Jurkat cells

   PMID:8457378

   Open questions at the time

   • No structural basis for DNA recognition
   • Whether endogenous full-length RPL6 binds this element in vivo not shown
2. 1998 Medium

   Defined RPL6 as an intracellular FGF-2 binding partner with mapped binding domains, linking it to growth-factor signaling and Tax transactivation.

   Evidence Yeast two-hybrid, in vitro binding, deletion mapping, transactivation assay

   PMID:9826564

   Open questions at the time

   • Functional consequence of FGF-2 binding not mechanistically resolved
   • Single lab
3. 2002 Medium

   Showed RPL6 directly binds the HTLV-1 Tax protein, suggesting it modulates viral transactivation.

   Evidence Yeast two-hybrid and GST pull-down

   PMID:12007002

   Open questions at the time

   • No demonstration of effect on Tax-driven transcription in this study
   • Abstract-level reporting
4. 2011 Medium

   Placed RPL6 upstream of cyclin E in driving G1/S progression, establishing a cell-cycle role.

   Evidence siRNA knockdown with flow cytometry and Western blot in two gastric cancer lines

   PMID:22043320

   Open questions at the time

   • Mechanism linking RPL6 to cyclin E expression unresolved
   • Confined to gastric cancer cells
5. 2018 High

   Defined a clear DNA-damage-response function: RPL6 is PARP-dependently recruited to damage sites and is required for the MDC1–γH2AX axis and downstream RNF168/53BP1/BRCA1 signaling.

   Evidence Co-IP, fractionation, His-ubiquitin pulldown, immunofluorescence, siRNA, checkpoint assays

   PMID:30598506

   Open questions at the time

   • Direct structural mode of damage-site recruitment unknown
   • How ribosomal vs extraribosomal RPL6 pools are partitioned not defined
6. 2019 Medium

   Connected RPL6 to RNA methylation and germline biology through partners NSUN2 (human) and Srlp (Drosophila), implicating it in translational control of partner proteins.

   Evidence Reciprocal Co-IP and rescue in gallbladder carcinoma cells; LC-MS/MS interactome and genetics in Drosophila

   PMID:30931935 PMID:31487418

   Open questions at the time

   • Whether RPL6 directly controls NSUN2 translation not proven
   • Drosophila ortholog generalization uncertain
7. 2022 Medium

   Identified post-translational control of RPL6 abundance and its link to p53: UBE2T drives K48-linked degradation that modulates p53 activity.

   Evidence Ubiquitination assays, knockdown/overexpression, xenografts (UBE2T); AKT pathway marker analysis (lung cancer)

   PMID:35280491 PMID:36156329

   Open questions at the time

   • E3-independent ubiquitination mechanism unusual and not fully explained
   • AKT linkage is correlative without direct mechanism
8. 2025 Medium

   Expanded RPL6 functions into mRNA stabilization, multiple oncogenic signaling axes, and innate immunity through direct partner interactions.

   Evidence RNA pulldown/3'UTR binding and HCC models (HMGCS1/HIF-1α); MS+Co-IP with EIF2B5 (PI3K/AKT/mTOR); biochemical binding and OPP labeling with CacyBP/SIP; Co-IP with cGAS (cGAS-STING/IFN-β)

   PMID:40246131 PMID:40650669 PMID:40691326 PMID:41318619

   Open questions at the time

   • Whether these distinct functions involve the same or different RPL6 pools unresolved
   • cGAS interaction reported at abstract level with limited follow-up
9. 2025 Medium

   Showed that ribosome-free RPL6 is a preferred HPF1-dependent PARP1/2 ADP-ribosylation substrate, providing a biochemical basis for regulation of its extraribosomal pool.

   Evidence Reconstituted in vitro ADP-ribosylation with labeled NAD+ and ribosome-bound negative control (preprint)

   PMID:bio_10.1101_2025.09.15.676193

   Open questions at the time

   • In vivo occurrence and functional consequence of RPL6 ADP-ribosylation not established
   • Preprint, single lab

• How RPL6 is partitioned and regulated between its ribosomal role and its many extraribosomal functions, and the structural basis for its diverse DNA, RNA, and protein interactions, remain unresolved.
• No structural model for the extraribosomal interactions
• Mechanism controlling the free vs ribosome-bound RPL6 pool unknown