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

Tripathi, Vivek and Agarwal, Himanshi and Priya, Swati and Batra, Harish and Modi, Priyanka and Pandey, Monica and Saha, Dhurjhoti and Raghavan, Sathees C and Sengupta, Sagar (2018) MRN complex-dependent recruitment of ubiquitylated BLM helicase to DSBs negatively regulates DNA repair pathways. In: NATURE COMMUNICATIONS, 9 .

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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.

Item Type:	Journal Article
Publication:	NATURE COMMUNICATIONS
Publisher:	NATURE PUBLISHING GROUP, MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
Additional Information:	Copy right for the article belong to NATURE PUBLISHING GROUP, MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
Department/Centre:	Division of Biological Sciences > Biochemistry
Date Deposited:	02 Apr 2018 19:58
Last Modified:	02 Apr 2018 19:58
URI:	http://eprints.iisc.ac.in/id/eprint/59444

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