MRN complex-dependent recruitment of ubiquitylated BLM helicase to DSBs negatively regulates DNA repair pathways

Vivek Tripathi, Himanshi Agarwal, Swati Priya, Harish Batra, Priyanka Modi, Monica Pandey, Dhurjhoti Saha, Sathees C. Raghavan and Sagar Sengupta ()
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Vivek Tripathi: National Institute of Immunology
Himanshi Agarwal: National Institute of Immunology
Swati Priya: National Institute of Immunology
Harish Batra: National Institute of Immunology
Priyanka Modi: National Institute of Immunology
Monica Pandey: Indian Institute of Science
Dhurjhoti Saha: Institute of Genomics and Integrative Biology, CSIR
Sathees C. Raghavan: Indian Institute of Science
Sagar Sengupta: National Institute of Immunology

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract Mutations in BLM in Bloom Syndrome patients predispose them to multiple types of cancers. Here we report that BLM is recruited in a biphasic manner to annotated DSBs. BLM recruitment is dependent on the presence of NBS1, MRE11 and ATM. While ATM activity is essential for BLM recruitment in early phase, it is dispensable in late phase when MRE11 exonuclease activity and RNF8-mediated ubiquitylation of BLM are the key determinants. Interaction between polyubiquitylated BLM and NBS1 is essential for the helicase to be retained at the DSBs. The helicase activity of BLM is required for the recruitment of HR and c-NHEJ factors onto the chromatin in S- and G1-phase, respectively. During the repair phase, BLM inhibits HR in S-phase and c-NHEJ in G1-phase. Consequently, inhibition of helicase activity of BLM enhances the rate of DNA alterations. Thus BLM utilizes its pro- and anti-repair functions to maintain genome stability.

Date: 2018
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DOI: 10.1038/s41467-018-03393-8

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