The deSUMOylase SENP2 coordinates homologous recombination and nonhomologous end joining by independent mechanisms

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@article{1b7886b68dd44910b4cba7716324d87b,
title = "The deSUMOylase SENP2 coordinates homologous recombination and nonhomologous end joining by independent mechanisms",
abstract = "SUMOylation (small ubiquitin-like modifier) in the DNA double-strand break (DSB) response regulates recruitment, activity, and clearance of repair factors. However, our understanding of a role for deSUMOylation in this process is limited. Here we identify different mechanistic roles for deSUMOylation in homologous recombination (HR) and nonhomologous end joining (NHEJ) through the investigation of the deSUMOylase SENP2. We found that regulated deSUMOylation of MDC1 prevents excessive SUMOylation and its RNF4-VCP mediated clearance from DSBs, thereby promoting NHEJ. In contrast, we show that HR is differentially sensitive to SUMO availability and SENP2 activity is needed to provide SUMO. SENP2 is amplified as part of the chromosome 3q amplification in many cancers. Increased SENP2 expression prolongs MDC1 focus retention and increases NHEJ and radioresistance. Collectively, our data reveal that deSUMOylation differentially primes cells for responding to DSBs and demonstrates the ability of SENP2 to tune DSB repair responses.",
keywords = "DNA repair, homologous recombination, MDC1, nonhomologous end joining, RNF4, SENP2, SUMO",
author = "Garvin, {Alexander J.} and Walker, {Alexandra K.} and Densham, {Ruth M.} and Chauhan, {Anoop Singh} and Stone, {Helen R.} and Mackay, {Hannah L.} and Mohammed Jamshad and Katarzyna Starowicz and Manuel Daza-Martin and Ronson, {George E.} and Lanz, {Alexander J.} and Beesley, {James F.} and Morris, {Joanna R.}",
note = "{\textcopyright} 2019 Garvin et al.; Published by Cold Spring Harbor Laboratory Press.",
year = "2019",
month = feb
day = "22",
doi = "10.1101/gad.321125.118",
language = "English",
volume = "33",
pages = "333--347",
journal = "Genes & Development",
issn = "0890-9369",
publisher = "Cold Spring Harbor Laboratory Press",
number = "5-6",

}

RIS

TY - JOUR

T1 - The deSUMOylase SENP2 coordinates homologous recombination and nonhomologous end joining by independent mechanisms

AU - Garvin, Alexander J.

AU - Walker, Alexandra K.

AU - Densham, Ruth M.

AU - Chauhan, Anoop Singh

AU - Stone, Helen R.

AU - Mackay, Hannah L.

AU - Jamshad, Mohammed

AU - Starowicz, Katarzyna

AU - Daza-Martin, Manuel

AU - Ronson, George E.

AU - Lanz, Alexander J.

AU - Beesley, James F.

AU - Morris, Joanna R.

N1 - © 2019 Garvin et al.; Published by Cold Spring Harbor Laboratory Press.

PY - 2019/2/22

Y1 - 2019/2/22

N2 - SUMOylation (small ubiquitin-like modifier) in the DNA double-strand break (DSB) response regulates recruitment, activity, and clearance of repair factors. However, our understanding of a role for deSUMOylation in this process is limited. Here we identify different mechanistic roles for deSUMOylation in homologous recombination (HR) and nonhomologous end joining (NHEJ) through the investigation of the deSUMOylase SENP2. We found that regulated deSUMOylation of MDC1 prevents excessive SUMOylation and its RNF4-VCP mediated clearance from DSBs, thereby promoting NHEJ. In contrast, we show that HR is differentially sensitive to SUMO availability and SENP2 activity is needed to provide SUMO. SENP2 is amplified as part of the chromosome 3q amplification in many cancers. Increased SENP2 expression prolongs MDC1 focus retention and increases NHEJ and radioresistance. Collectively, our data reveal that deSUMOylation differentially primes cells for responding to DSBs and demonstrates the ability of SENP2 to tune DSB repair responses.

AB - SUMOylation (small ubiquitin-like modifier) in the DNA double-strand break (DSB) response regulates recruitment, activity, and clearance of repair factors. However, our understanding of a role for deSUMOylation in this process is limited. Here we identify different mechanistic roles for deSUMOylation in homologous recombination (HR) and nonhomologous end joining (NHEJ) through the investigation of the deSUMOylase SENP2. We found that regulated deSUMOylation of MDC1 prevents excessive SUMOylation and its RNF4-VCP mediated clearance from DSBs, thereby promoting NHEJ. In contrast, we show that HR is differentially sensitive to SUMO availability and SENP2 activity is needed to provide SUMO. SENP2 is amplified as part of the chromosome 3q amplification in many cancers. Increased SENP2 expression prolongs MDC1 focus retention and increases NHEJ and radioresistance. Collectively, our data reveal that deSUMOylation differentially primes cells for responding to DSBs and demonstrates the ability of SENP2 to tune DSB repair responses.

KW - DNA repair

KW - homologous recombination

KW - MDC1

KW - nonhomologous end joining

KW - RNF4

KW - SENP2

KW - SUMO

UR - http://www.scopus.com/inward/record.url?scp=85063298068&partnerID=8YFLogxK

U2 - 10.1101/gad.321125.118

DO - 10.1101/gad.321125.118

M3 - Article

C2 - 30796017

VL - 33

SP - 333

EP - 347

JO - Genes & Development

JF - Genes & Development

SN - 0890-9369

IS - 5-6

ER -