Nath, S and Nagaraju, G (2020) FANCJ helicase promotes DNA end resection by facilitating CtIP recruitment to DNA double-strand breaks. In: PLoS Genetics, 16 (4).
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Abstract
FANCJ helicase mutations are known to cause hereditary breast and ovarian cancers as well as bone marrow failure syndrome Fanconi anemia. FANCJ plays an important role in the repair of DNA inter-strand crosslinks and DNA double-strand breaks (DSBs) by homologous recombination (HR). Nonetheless, the molecular mechanism by which FANCJ controls HR mediated DSB repair is obscure. Here, we show that FANCJ promotes DNA end resection by recruiting CtIP to the sites of DSBs. This recruitment of CtIP is dependent on FANCJ K1249 acetylation. Notably, FANCJ acetylation is dependent on FANCJ S990 phosphorylation by CDK. The CDK mediated phosphorylation of FANCJ independently facilitates its interaction with BRCA1 at damaged DNA sites and promotes DNA end resection by CtIP recruitment. Strikingly, mutational studies reveal that ATP binding competent but hydrolysis deficient FANCJ partially supports end resection, indicating that in addition to the scaffolding role of FANCJ in CtIP recruitment, its helicase activity is important for promoting end resection. Together, these data unravel a novel function of FANCJ helicase in DNA end resection and provide mechanistic insights into its role in repairing DSBs by HR and in genome maintenance. © 2020 Nath, Nagaraju. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
| Item Type: | Journal Article |
|---|---|
| Publication: | PLoS Genetics |
| Publisher: | Public Library of Science |
| Additional Information: | The copyright for this article belongs to the Authors. |
| Keywords: | adenosine triphosphate; binding protein; BRCA1 protein; CtIP protein; cyclin dependent kinase; double stranded DNA; FANCJ helicase; helicase; lysine; serine; unclassified drug; adenosine triphosphate; BRCA1 protein; BRCA1 protein, human; BRIP1 protein, human; cyclin dependent kinase; deoxyribonuclease; Fanconi anemia protein; RBBP8 protein, human; RNA helicase, Article; controlled study; DNA end resection; DNA structure; double stranded DNA break; enzymatic hydrolysis; enzyme activity; enzyme phosphorylation; genome; human; human cell; mutation; nucleotide binding site; protein acetylation; genetics; metabolism; tumor cell line, Adenosine Triphosphate; BRCA1 Protein; Cell Line, Tumor; Cyclin-Dependent Kinases; DNA Breaks, Double-Stranded; Endodeoxyribonucleases; Fanconi Anemia Complementation Group Proteins; Humans; RNA Helicases |
| Department/Centre: | Division of Biological Sciences > Biochemistry |
| Date Deposited: | 24 Jan 2023 05:09 |
| Last Modified: | 24 Jan 2023 05:09 |
| URI: | https://eprints.iisc.ac.in/id/eprint/79379 |
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