The cell cycle flavours of repair

Zlotorynski, Eytan

doi:10.1038/nrm.2015.24

Research Highlight
Published: 23 December 2015

DNA repair

The cell cycle flavours of repair

Eytan Zlotorynski

Nature Reviews Molecular Cell Biology volume 17, page 65 (2016)Cite this article

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HR is tightly suppressed in G1 owing to the lack of sister chromatids that can serve as accurate repair templates. This is mediated by p53-binding protein 1 (53BP1), which prevents the recruitment of the BRCA1–PALB2 (partner and localizer of BRCA2)–BRCA2 complex and thus of other HR factors to double-strand breaks (DSBs) in G1. Orthwein et al. found that PALB2 and BRCA2 were not recruited to DSBs in G1 even in human cells not expressing 53BP1, owing to a lack of BRCA1–PALB2 association. A region in PALB2 that mediates its interaction with kelch-like ECH-associated protein 1 (KEAP1) was identified as being responsible for the BRCA1–PALB2 interaction. KEAP1 is a substrate adaptor (recruiter) for the E3 ubiquitin ligase CRL3 (cullin 3 (CUL3)–RING ubiquitin ligase), and PALB2 ubiquitylation by CRL3 at Lys20, Lys25 and Lys30 prevented its interaction with BRCA1. In cells lacking KEAP1 or KEAP1–CUL3 association, stable BRCA1–PALB2–BRCA2 complexes were detected at DSBs also in G1.

As neither CRL3–KEAP1 activity nor its interaction with PALB2 is cell cycle regulated, the authors examined whether the KEAP1-, PALB2- and BRCA2-interacting deubiquitylase USP11, which is a HR factor of unknown function, is cell cycle regulated. USP11 was necessary for the formation of stable BRCA1–PALB2–BRCA2 complexes, but following the induction of DSBs in G1, it was ubiquitylated and degraded by the proteasome. Thus, the cell cycle-regulated expression of USP11 controls recruitment by BRCA1 of HR factors to DSBs.

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References

Minocherhomji, S. et al. Replication stress activates DNA repair synthesis in mitosis. Nature 528, 286–290 (2015)
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Orthwein, A. et al. A mechanism for the suppression of homologous recombination in G1 cells. Nature http://dx.doi.org/10.1038/nature16142 (2015)

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