CHAMP1 binds to REV7/FANCV and promotes homologous recombination repair

Li, Feng; Sarangi, Prabha; Iyer, Divya Ramalingam; Feng, Hanrong; Moreau, Lisa A.; Nguyen, Huy; Clairmont, Connor S.; D’Andrea, Alan D.

doi:10.1016/j.celrep.2022.111297

Cited by 12 publications

(14 citation statements)

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“…The Shieldin complex is localized to sites of DNA DSBs where it inhibits DSB end-resection, blocks HR, and promotes NHEJ ( 12 – 21 ). Disruption of the Shieldin complex, either by knockout of REV7, SHLD1, SHLD2, or SHLD3, or by overexpression of TRIP13 ATPase or of CHAMP1, results in enhanced DSB end-resection and HR repair ( 27 , 39 – 41 ).…”

Section: Resultsmentioning

confidence: 99%

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CCAR2 functions downstream of the Shieldin complex to promote double-strand break end-joining

Iyer

Harada

Clairmont

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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The 53BP1-RIF1 pathway restricts the resection of DNA double-strand breaks (DSBs) and promotes blunt end-ligation by non-homologous end joining (NHEJ) repair. The Shieldin complex is a downstream effector of the 53BP1-RIF1 pathway. Here, we identify a component of this pathway, CCAR2/DBC1, which is also required for restriction of DNA end-resection. CCAR2 co-immunoprecipitates with the Shieldin complex, and knockout of CCAR2 in a BRCA1-deficient cell line results in elevated DSB end-resection, RAD51 loading, and PARP inhibitor (PARPi) resistance. Knockout of CCAR2 is epistatic with knockout of other Shieldin proteins. The S1-like RNA-binding domain of CCAR2 is required for its interaction with the Shieldin complex and for suppression of DSB end-resection. CCAR2 functions downstream of the Shieldin complex, and CCAR2 knockout cells have delayed resolution of Shieldin complex foci. Forkhead-associated (FHA)-dependent targeting of CCAR2 to DSB sites re-sensitized BRCA1−/−SHLD2−/− cells to PARPi. Taken together, CCAR2 is a functional component of the 53BP1-RIF1 pathway, promotes the refill of resected DSBs, and suppresses homologous recombination.

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Section: Resultsmentioning

confidence: 99%

“…S1 A ). In our previous work, we had demonstrated that REV7 exists in two conformation (open and closed) and that the closed conformation binds to the seat–belt interactors SHLD3, REV3, and CHAMP1 ( 27 , 41 ). The AAA+ATPase TRIP13 catalyzes the conversion of closed-REV7 to open-REV7 ( 27 ).…”

Section: Resultsmentioning

confidence: 99%

CCAR2 functions downstream of the Shieldin complex to promote double-strand break end-joining

Iyer

Harada

Clairmont

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…Inhibitory effects on REV7 are provoked by chromosome alignment-maintaining phosphoprotein 1 (CHAMP1) and p31 comet –TRIP13. CHAMP1, which is involved in microtubule organization, binds to REV7 and reduces the Shieldin complex activity to promote 5’ end resection and HR repair at DSBs [ 71 , 72 ]. p31 comet -TRIP13 binds to REV7 in the Shieldin complex and promotes its dissociation from SHLD3 by inducing O-REV7 from C-REV7, resulting in a reduction in the Shieldin complex activity ( Figure 3 ) [ 29 , 30 ].…”

Section: Rev7 In Other Dna Repair Pathwaysmentioning

confidence: 99%

REV7 in Cancer Biology and Management

Murakumo

Sakurai

Kato

et al. 2023

Cancers

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DNA repair and cell cycle regulation are potential biological fields to develop molecular targeting therapies for cancer. Human REV7 was originally discovered as a homologous molecule to yeast Rev7, which is involved in DNA damage response and mutagenesis, and as the second homolog of yeast Mad2, involved in the spindle assembly checkpoint. Although REV7 principally functions in the fields of DNA repair and cell cycle regulation, many binding partners of REV7 have been identified using comprehensive analyses in the past decade, and the significance of REV7 is expanding in various other biological fields, such as gene transcription, epigenetics, primordial germ cell survival, neurogenesis, intracellular signaling, and microbial infection. In addition, the clinical significance of REV7 has been demonstrated in studies using human cancer tissues, and investigations in cancer cell lines and animal models have revealed the greater impacts of REV7 in cancer biology, which makes it an attractive target molecule for cancer management. This review focuses on the functions of REV7 in human cancer and discusses the utility of REV7 for cancer management with a summary of the recent development of inhibitors targeting REV7.

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“…The FA pathway can be divided into four major modules: lesion recognition, upstream core complex recruitment, FANCD2–FANCI complex monoubiquitination, and downstream protein recruitment [22]. The genes involved in the FA pathway have been identified as FANCA [23], FANCB [24], FANCC [25], FANCD1 / BRCA2 [26], FANCD2 [27], FANCE [28], FANCF [29], FANCG [30], FANCI [31], FANCJ / BRIP1 / BACH1 [32], FANCL [33], FANCM [34], FANCN [35], FANCO / RAD51C [36], FANCP / SLX4 [37], FANCQ / ERCC4 / XPF [38], FANCR / RAD51 [39], FANCS / BRCA1 [40], FANCT / UBE2T [41], FANCU / XRCC2 [36], FANCV / REV7 / MAD2L2 [42], and FANCW / RFWD3 [43]. The lesion-recognition process is completed by FANCM, whereas FAAP24 binds to FANCM to form ligands that specifically target DNA damage sites and participate in DNA damage repair [44].…”

Section: Regulatory Function Of Fa Pathway Genes In Dna Damage Repairmentioning

confidence: 99%

Research progress of the Fanconi anemia pathway and premature ovarian insufficiency

Zhao,

Zhang,

et al. 2023

Biology of Reproduction

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The Fanconi anemia pathway is a key pathway involved in the repair of deoxyribonucleic acidinterstrand crosslinking damage, which chiefly includes the following four modules: lesion recognition, Fanconi anemia core complex recruitment, FANCD2–FANCI complex monoubiquitination, and downstream events (nucleolytic incision, translesion synthesis, and homologous recombination). Mutations or deletions of multiple Fanconi anemia genes in this pathway can damage the interstrand crosslinking repair pathway and disrupt primordial germ cell development and oocyte meiosis, thereby leading to abnormal follicular development. Premature ovarian insufficiency is a gynecological clinical syndrome characterized by amenorrhea and decreased fertility due to decreased oocyte pool, accelerated follicle atresia, and loss of ovarian function in women <40 years old. Furthermore, in recent years, several studies have detected mutations in the Fanconi anemia gene in patients with premature ovarian insufficiency. In addition, some patients with Fanconi anemia exhibit symptoms of premature ovarian insufficiency and infertility. The Fanconi anemia pathway and premature ovarian insufficiency are closely associated.

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CHAMP1 binds to REV7/FANCV and promotes homologous recombination repair

Cited by 12 publications

References 50 publications

CCAR2 functions downstream of the Shieldin complex to promote double-strand break end-joining

CCAR2 functions downstream of the Shieldin complex to promote double-strand break end-joining

REV7 in Cancer Biology and Management

Research progress of the Fanconi anemia pathway and premature ovarian insufficiency

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