Ask about this productRelated genes to: MAD2L2 antibody
- Gene:
- MAD2L2 NIH gene
- Name:
- mitotic arrest deficient 2 like 2
- Previous symbol:
- -
- Synonyms:
- MAD2B, REV7, POLZ2, FANCV
- Chromosome:
- 1p36.22
- Locus Type:
- gene with protein product
- Date approved:
- 1999-06-22
- Date modifiied:
- 2018-03-23
Related products to: MAD2L2 antibody
Related articles to: MAD2L2 antibody
- Source: PubMed
- DNA double-strand break (DSB) is a highly toxic lesion that can generate genome instability, a major source of tumorigenesis. DSBs are mainly repaired by non-homologous end joining (NHEJ) or homologous recombination (HR). The selection of the DSB repair pathway primarily depends on the DNA resection of the DSB ends. Indeed, HR is initiated by resection at the DSB, generating 3' single-stranded overhang. The shieldin complex prevents resection fostering DSB repair toward NHEJ. Here, we reveal that the inflammasome sensor NLRP3 facilitates DNA end resection to promote the HR pathway in an inflammasome-independent manner. Strikingly, NLRP3 silencing decreases HR efficiency, as evidenced by RAD51 foci and functional HR assays. Mechanistically, we describe that NLRP3 interacts with REV7, a subunit of the shieldin complex, and its depletion increases REV7 recruitment to IR-induced DSBs. Similar to cancer cells harboring HR-mutated genes, we find that NLRP3-deficient cells are sensitive to Poly-ADP-ribose polymerase (PARP) inhibitors (PARPi) and exhibit an epistatic relationship with BRCA1 deficiency. Remarkably, loss of REV7 in NLRP3-depleted cells induces PARPi resistance by restoring HR. This study unravels the crucial role of the innate immune receptor NLRP3 in regulating the selection of DSB repair pathways to maintain genome integrity. - Source: PubMed
Burlet DelphineKhan Md MuntazHacot SabineButhmann HannesBardoulet LéaHuber Anne-LaureGorry JulieFöhr BastianLopez Bernard SCouté YohannFaesen Alex CGeyer MatthiasTissier AgnèsPetrilli Virginie - Glioblastoma (GB) is a highly aggressive brain tumor resistant to chemoradiotherapy, largely due to glioma stem-like cells (GSCs) with robust DNA damage repair capabilities. Here we reveal that GSCs enhance their DNA repair capacity by activating non-homologous end-joining (NHEJ) through upregulation of the apoptosis antagonizing transcription factor (AATF), thereby promoting therapeutic resistance in GB. AATF interacts with XRCC4, a core NHEJ subunit, preventing its degradation via ubiquitin-mediated proteasomal processes. Upon DNA damage, AATF undergoes phosphorylation at Ser189 by ATM, leading to its dissociation from XRCC4 and rapid recruitment of XRCC4 to DNA break sites for efficient NHEJ repair. Moreover, AATF depletion or deficient AATF phosphorylation impedes NHEJ in GSCs, sensitizing GB xenografts to chemoradiotherapy. Additionally, elevated levels of AATF inform poor prognosis in GB patients. Collectively, our findings unveil a crucial role of AATF in XRCC4-mediated NHEJ repair, and underscore targeting AATF as a potential strategy to overcome GB resistance to chemoradiotherapy. - Source: PubMed
Publication date: 2025/05/28
Mi LanjuanCai YanQi JiChen LishuLi YuanyuanZhang SongyangRan HaowenQi QinghuiZhang ChengWu HuiranCao ShuailiangHuang HaohaoXiao DakeWang XinzhengLi BohanXie JiongLi FangyeHan QiuyingWu QiulianLi TaoLi AilingRich Jeremy NZhou TaoMan Jianghong - Downstream of 53BP1-RIF1 lies the Shieldin (SHLD) protein complex, which comprises MAD2L2/REV7, SHLD3, SHLD2, and SHLD1, and the CTC1-STN1-TEN1 (CST) complex. During immunoglobulin heavy-chain (Igh) class switch recombination (CSR), 53BP1-RIF1-SHLD promotes productive end-joining by limiting resection of activation-induced cytidine deaminase (AID)-generated DNA double-strand break (DSB) ends. The precise role of the CST complex and its interplay with SHLD during CSR is however elusive. Here, we established AID-inducible B cell lines deficient for CTC1, SHLD1, or both and analyzed CSR in these cells. We show that stimulated CTC1-deficient B cells are defective for IgM-to-IgA class switching, accumulate Igh chromosome breaks and translocations, and display increased end-resection and micro-homology usage at switching sites, demonstrating that CTC1 is essential to suppress alternative end-joining during CSR. We show that CTC1 and SHLD1 are epistatic in preventing exacerbated DNA end resection and genetic instability during CSR. Moreover, using a complementation approach in Shld1 knockout splenic B cells, we show that a SHLD1 mutant defective in CST binding (SHLD1) is fully proficient for IgM-to-IgG1, IgG2b, IgG3, and IgA class switching, thus demonstrating that the SHLD1-CTC1 interaction through this motif is dispensable for CST and SHLD functions in promoting CSR. - Source: PubMed
Lescale ChloéMarton TimeaVaysse AmauryRode GuillaumeVincendeau EstelleLibri AliceDossin FrançoisDeriano Ludovic - REV7, also named MAD2B or MAD2L2, is a subunit of the DNA translesion polymerase zeta and also part of the 53BP1-shieldin complex, which is present at sites of DNA double-strand breaks. REV7 has high sequence similarity to the MAD2 spindle assembly checkpoint protein, prompting us to examine whether REV7 has a checkpoint function. We observed that, in chicken and human cells exposed to agents that induce DNA replication stress, REV7 inhibits mitotic entry; this effect is most evident when the canonical DNA replication stress checkpoint, mediated by ATR, is inhibited. Similar to MAD2, REV7 undergoes conformational changes upon ligand binding, and its checkpoint function depends on its ability to homodimerize and bind its ligands. Notably, even in unchallenged cells, deletion of the REV7 gene leads to premature mitotic entry, raising the possibility that the REV7 checkpoint monitors ongoing DNA replication. - Source: PubMed
Publication date: 2025/03/18
Sobkowiak KatarzynaKohzaki MasaokiBöhm RaphaelMailler JonathanHuber FlorianEmamzadah SoheilaTropia LaurenceHiller SebastianHalazonetis Thanos D