REV7: Jack of many trades

Krijger, Inge de; Boersma, Vera; Jacobs, Jacqueline J.L.

doi:10.1016/j.tcb.2021.04.002

Cited by 39 publications

(32 citation statements)

References 117 publications

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“…Finally, in addition to its role in TLS, MAD2L2 has central roles in different cellular pathways [24]. Recently, it was found to be part of the shieldin complex, promoting nonhomologous end-joining and inhibiting homologous recombination (HR) [25][26][27].…”

Section: Discussionmentioning

confidence: 99%

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Disrupting the MAD2L2-Rev1 Complex Enhances Cell Death upon DNA Damage

et al. 2022

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DNA-damaging chemotherapy agents such as cisplatin have been the first line of treatment for cancer for decades. While chemotherapy can be very effective, its long-term success is often reduced by intrinsic and acquired drug resistance, accompanied by chemotherapy-resistant secondary malignancies. Although the mechanisms causing drug resistance are quite distinct, they are directly connected to mutagenic translesion synthesis (TLS). The TLS pathway promotes DNA damage tolerance by supporting both replication opposite to a lesion and inaccurate single-strand gap filling. Interestingly, inhibiting TLS reduces both cisplatin resistance and secondary tumor formation. Therefore, TLS targeting is a promising strategy for improving chemotherapy. MAD2L2 (i.e., Rev7) is a central protein in TLS. It is an essential component of the TLS polymerase zeta (ζ), and it forms a regulatory complex with Rev1 polymerase. Here we present the discovery of two small molecules, c#2 and c#3, that directly bind both in vitro and in vivo to MAD2L2 and influence its activity. Both molecules sensitize lung cancer cell lines to cisplatin, disrupt the formation of the MAD2L2-Rev1 complex and increase DNA damage, hence underlining their potential as lead compounds for developing novel TLS inhibitors for improving chemotherapy treatments.

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Section: Discussionmentioning

confidence: 99%

“…Moreover, recent evidence links mutations in the shieldin complex to resistance to PARP inhibitors in BRCA 1/2-deficient cells [30,31]. Moreover, MAD2L2 overexpression was found in several cancer types and is correlated with poor prognosis [24,32,33].…”

Section: Discussionmentioning

confidence: 99%

Disrupting the MAD2L2-Rev1 Complex Enhances Cell Death upon DNA Damage

et al. 2022

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“…Moreover, depletion of 53BP1 in Ligase IV-deficient G0/G1-blocked pro-B cells results in increased levels of resection at irradiation-induced DSB ends, demonstrating that 53BP1 is crucial for DNA end protection in this cell-cycle phase ( Figure 2Cii ) ( Chen B. R. et al, 2021 ). The Shieldin complex, composed of SHLD1, SHLD2, SHLD3 and MAD2L2/REV7, acts downstream of 53BP1-RIF1 to antagonize DNA end resection and favor NHEJ over HR ( Greenberg, 2018 ; Setiaputra and Durocher, 2019 ; Mirman and de Lange, 2020 ; de Krijger et al, 2021 ). It acts in a paradoxical manner as it requires to bind >50 nt-long ssDNA ends in order to hinder DNA end resection ( Dev et al, 2018 ; Findlay et al, 2018 ; Gao et al, 2018 ; Noordermeer et al, 2018 ).…”

Section: Blocking Dna End Resection and (Micro)homology-driven Double-strand Break Repairmentioning

confidence: 99%

The (Lack of) DNA Double-Strand Break Repair Pathway Choice During V(D)J Recombination

2022

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DNA double-strand breaks (DSBs) are highly toxic lesions that can be mended via several DNA repair pathways. Multiple factors can influence the choice and the restrictiveness of repair towards a given pathway in order to warrant the maintenance of genome integrity. During V(D)J recombination, RAG-induced DSBs are (almost) exclusively repaired by the non-homologous end-joining (NHEJ) pathway for the benefit of antigen receptor gene diversity. Here, we review the various parameters that constrain repair of RAG-generated DSBs to NHEJ, including the peculiarity of DNA DSB ends generated by the RAG nuclease, the establishment and maintenance of a post-cleavage synaptic complex, and the protection of DNA ends against resection and (micro)homology-directed repair. In this physiological context, we highlight that certain DSBs have limited DNA repair pathway choice options.

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“…REV7 (also known as MAD2L2, MAD2B, or FANCV) is a highly conserved member of the HORMA family of proteins, named for its three founding members: HOp1, a meiotic chromosome axis factor, REV7, and MAD2, a spindle assembly checkpoint protein ( Clairmont and D’Andrea, 2021 ; de Krijger et al, 2021a ). REV7 is an abundant cellular protein and is unique among HORMA proteins, both in its large number of binding partners and in its involvement in multiple distinct pathways.…”

Section: Introductionmentioning

confidence: 99%