CHAMP1-POGZ counteracts the inhibitory effect of 53BP1 on homologous recombination and affects PARP inhibitor resistance

Fujita, Hiroki; Ikeda, Masanori; Ui, Ayako; Ouchi, Yunosuke; Mikami, Yoshiko; Kanno, Shin-ichiro; Yasui, Akira; Tanaka, Kozo

doi:10.1038/s41388-022-02299-6

Cited by 10 publications

(16 citation statements)

References 69 publications

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“…A recent study published during the review of our manuscript independently confirmed our finding that CHAMP1 and REV7 interact and promote HR ( Fujita et al, 2022 ). According to this work, CHAMP1 is recruited to laser stripes following DNA damage, and CHAMP1 promotes DNA DSB end resection and pRPA loading.…”

Section: Discussionsupporting

confidence: 85%

CHAMP1 binds to REV7/FANCV and promotes homologous recombination repair

Sarangi

Iyer

et al. 2022

Cell Reports

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Section: Discussionsupporting

confidence: 85%

CHAMP1 binds to REV7/FANCV and promotes homologous recombination repair

Sarangi

Iyer

et al. 2022

Cell Reports

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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%

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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“…7A and B ), suggesting that CHAMP1 is required for the stability of POGZ, which was also shown in a recent report. 53 We also studied axon outgrowth in CHAMP1 knockdown neurons by measuring the number of axons stained with ankyrin-G, a marker of the axon initial segment, which were also positive for Map2, a dendritic marker. As shown in Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“… 59 POGZ is also involved in DNA double-strand break (DSB) repair, 60 and we recently reported that CHAMP1 functions in DSB repair together with POGZ. 53 POGZ is widely expressed in neurons throughout the brain. 25 , 49 , 50 POGZ homozygous knockout mice die during embryonic development or shortly after birth.…”

Section: Discussionmentioning

confidence: 99%

Deficiency of CHAMP1, a gene related to intellectual disability, causes impaired neuronal development and a mild behavioural phenotype

Nagai

Iemura

Kikkawa

et al. 2022

Brain Communications

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CHAMP1 is a gene associated with intellectual disability, which was originally identified as being involved in the maintenance of kinetochore–microtubule attachment. To explore the neuronal defects caused by CHAMP1 deficiency, we established mice that lack CHAMP1. Mice that are homozygous knockout for CHAMP1 were slightly smaller than wild type mice and died soon after birth on pure C57BL/6J background. Although gross anatomical defects were not found in CHAMP1-/- mouse brains, mitotic cells were increased in the cerebral cortex. Neuronal differentiation was delayed in CHAMP1-/- neural stem cells in vitro, which was also suggested in vivo by CHAMP1 knockdown. In a behavioral test battery, adult CHAMP1 heterozygous-knockout mice showed mild memory defects, altered social interaction, and depression-like behaviors. In transcriptomic analysis, genes related to neurotransmitter transport and neurodevelopmental disorder were downregulated in embryonic CHAMP1-/- brains. These results suggest that CHAMP1 plays a role in neuronal development, and CHAMP1-deficient mice resemble some aspects of individuals with CHAMP1 mutations.

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CHAMP1-POGZ counteracts the inhibitory effect of 53BP1 on homologous recombination and affects PARP inhibitor resistance

Cited by 10 publications

References 69 publications

CHAMP1 binds to REV7/FANCV and promotes homologous recombination repair

CHAMP1 binds to REV7/FANCV and promotes homologous recombination repair

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

Deficiency of CHAMP1, a gene related to intellectual disability, causes impaired neuronal development and a mild behavioural phenotype

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