SLFN5-mediated chromatin dynamics sculpt higher-order DNA repair topology

Jinzhou Huang; Chenming Wu; Jake A. Kloeber; Huanyao Gao; Ming Gao; Qian Zhu; Yiming Chang; Fei Zhao; Guijie Guo; Kuntian Luo; Haiming Dai; Sijia Liu; Qiru Huang; Wootae Kim; Qin Zhou; Shouhai Zhu; Zheming Wu; Xinyi Tu; Ping Yin; Min Deng; Liewei Wang; Jian Yuan; Zhenkun Lou

doi:10.1016/j.molcel.2023.02.004

SLFN5-mediated chromatin dynamics sculpt higher-order DNA repair topology

Jinzhou Huang, Chenming Wu, Jake A. Kloeber, Huanyao Gao, Ming Gao, Qian Zhu, Yiming Chang, Fei Zhao, Guijie Guo, Kuntian Luo, Haiming Dai, Sijia Liu, Qiru Huang, Wootae Kim, Qin Zhou, Shouhai Zhu, Zheming Wu, Xinyi Tu, Ping Yin, Min DengLiewei Wang, Jian Yuan, Zhenkun Lou

Research output: Contribution to journal › Article › peer-review

Abstract

Repair of DNA double-strand breaks (DSBs) elicits three-dimensional (3D) chromatin topological changes. A recent finding reveals that 53BP1 assembles into a 3D chromatin topology pattern around DSBs. How this formation of a higher-order structure is configured and regulated remains enigmatic. Here, we report that SLFN5 is a critical factor for 53BP1 topological arrangement at DSBs. Using super-resolution imaging, we find that SLFN5 binds to 53BP1 chromatin domains to assemble a higher-order microdomain architecture by driving damaged chromatin dynamics at both DSBs and deprotected telomeres. Mechanistically, we propose that 53BP1 topology is shaped by two processes: (1) chromatin mobility driven by the SLFN5-LINC-microtubule axis and (2) the assembly of 53BP1 oligomers mediated by SLFN5. In mammals, SLFN5 deficiency disrupts the DSB repair topology and impairs non-homologous end joining, telomere fusions, class switch recombination, and sensitivity to poly (ADP-ribose) polymerase inhibitor. We establish a molecular mechanism that shapes higher-order chromatin topologies to safeguard genomic stability.

Original language	English (US)
Pages (from-to)	1043-1060.e10
Journal	Molecular Cell
Volume	83
Issue number	7
DOIs	https://doi.org/10.1016/j.molcel.2023.02.004
State	Published - Apr 6 2023

Keywords

53BP1
DNA double-strand break repair
PARP inhibitor sensitivity
SLFN5
chromatin mobility
chromatin topology
class switch recombination
non-homologous end joining
super-resolution microscopy
telomere fusions

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2023.02.004

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Huang, J, Wu, C, Kloeber, JA, Gao, H, Gao, M, Zhu, Q, Chang, Y, Zhao, F, Guo, G, Luo, K, Dai, H, Liu, S, Huang, Q, Kim, W, Zhou, Q, Zhu, S, Wu, Z, Tu, X, Yin, P, Deng, M, Wang, L, Yuan, J & Lou, Z 2023, 'SLFN5-mediated chromatin dynamics sculpt higher-order DNA repair topology', Molecular Cell, vol. 83, no. 7, pp. 1043-1060.e10. https://doi.org/10.1016/j.molcel.2023.02.004

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title = "SLFN5-mediated chromatin dynamics sculpt higher-order DNA repair topology",

abstract = "Repair of DNA double-strand breaks (DSBs) elicits three-dimensional (3D) chromatin topological changes. A recent finding reveals that 53BP1 assembles into a 3D chromatin topology pattern around DSBs. How this formation of a higher-order structure is configured and regulated remains enigmatic. Here, we report that SLFN5 is a critical factor for 53BP1 topological arrangement at DSBs. Using super-resolution imaging, we find that SLFN5 binds to 53BP1 chromatin domains to assemble a higher-order microdomain architecture by driving damaged chromatin dynamics at both DSBs and deprotected telomeres. Mechanistically, we propose that 53BP1 topology is shaped by two processes: (1) chromatin mobility driven by the SLFN5-LINC-microtubule axis and (2) the assembly of 53BP1 oligomers mediated by SLFN5. In mammals, SLFN5 deficiency disrupts the DSB repair topology and impairs non-homologous end joining, telomere fusions, class switch recombination, and sensitivity to poly (ADP-ribose) polymerase inhibitor. We establish a molecular mechanism that shapes higher-order chromatin topologies to safeguard genomic stability.",

keywords = "53BP1, DNA double-strand break repair, PARP inhibitor sensitivity, SLFN5, chromatin mobility, chromatin topology, class switch recombination, non-homologous end joining, super-resolution microscopy, telomere fusions",

author = "Jinzhou Huang and Chenming Wu and Kloeber, {Jake A.} and Huanyao Gao and Ming Gao and Qian Zhu and Yiming Chang and Fei Zhao and Guijie Guo and Kuntian Luo and Haiming Dai and Sijia Liu and Qiru Huang and Wootae Kim and Qin Zhou and Shouhai Zhu and Zheming Wu and Xinyi Tu and Ping Yin and Min Deng and Liewei Wang and Jian Yuan and Zhenkun Lou",

note = "Publisher Copyright: {\textcopyright} 2023 Elsevier Inc.",

year = "2023",

month = apr,

day = "6",

doi = "10.1016/j.molcel.2023.02.004",

language = "English (US)",

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pages = "1043--1060.e10",

journal = "Molecular Cell",

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TY - JOUR

T1 - SLFN5-mediated chromatin dynamics sculpt higher-order DNA repair topology

AU - Huang, Jinzhou

AU - Wu, Chenming

AU - Kloeber, Jake A.

AU - Gao, Huanyao

AU - Gao, Ming

AU - Zhu, Qian

AU - Chang, Yiming

AU - Zhao, Fei

AU - Guo, Guijie

AU - Luo, Kuntian

AU - Dai, Haiming

AU - Liu, Sijia

AU - Huang, Qiru

AU - Kim, Wootae

AU - Zhou, Qin

AU - Zhu, Shouhai

AU - Wu, Zheming

AU - Tu, Xinyi

AU - Yin, Ping

AU - Deng, Min

AU - Wang, Liewei

AU - Yuan, Jian

AU - Lou, Zhenkun

PY - 2023/4/6

Y1 - 2023/4/6

N2 - Repair of DNA double-strand breaks (DSBs) elicits three-dimensional (3D) chromatin topological changes. A recent finding reveals that 53BP1 assembles into a 3D chromatin topology pattern around DSBs. How this formation of a higher-order structure is configured and regulated remains enigmatic. Here, we report that SLFN5 is a critical factor for 53BP1 topological arrangement at DSBs. Using super-resolution imaging, we find that SLFN5 binds to 53BP1 chromatin domains to assemble a higher-order microdomain architecture by driving damaged chromatin dynamics at both DSBs and deprotected telomeres. Mechanistically, we propose that 53BP1 topology is shaped by two processes: (1) chromatin mobility driven by the SLFN5-LINC-microtubule axis and (2) the assembly of 53BP1 oligomers mediated by SLFN5. In mammals, SLFN5 deficiency disrupts the DSB repair topology and impairs non-homologous end joining, telomere fusions, class switch recombination, and sensitivity to poly (ADP-ribose) polymerase inhibitor. We establish a molecular mechanism that shapes higher-order chromatin topologies to safeguard genomic stability.

AB - Repair of DNA double-strand breaks (DSBs) elicits three-dimensional (3D) chromatin topological changes. A recent finding reveals that 53BP1 assembles into a 3D chromatin topology pattern around DSBs. How this formation of a higher-order structure is configured and regulated remains enigmatic. Here, we report that SLFN5 is a critical factor for 53BP1 topological arrangement at DSBs. Using super-resolution imaging, we find that SLFN5 binds to 53BP1 chromatin domains to assemble a higher-order microdomain architecture by driving damaged chromatin dynamics at both DSBs and deprotected telomeres. Mechanistically, we propose that 53BP1 topology is shaped by two processes: (1) chromatin mobility driven by the SLFN5-LINC-microtubule axis and (2) the assembly of 53BP1 oligomers mediated by SLFN5. In mammals, SLFN5 deficiency disrupts the DSB repair topology and impairs non-homologous end joining, telomere fusions, class switch recombination, and sensitivity to poly (ADP-ribose) polymerase inhibitor. We establish a molecular mechanism that shapes higher-order chromatin topologies to safeguard genomic stability.

KW - 53BP1

KW - DNA double-strand break repair

KW - PARP inhibitor sensitivity

KW - SLFN5

KW - chromatin mobility

KW - chromatin topology

KW - class switch recombination

KW - non-homologous end joining

KW - super-resolution microscopy

KW - telomere fusions

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U2 - 10.1016/j.molcel.2023.02.004

DO - 10.1016/j.molcel.2023.02.004

M3 - Article

C2 - 36854302

AN - SCOPUS:85150871689

SN - 1097-2765

VL - 83

SP - 1043-1060.e10

JO - Molecular Cell

JF - Molecular Cell

IS - 7

ER -

SLFN5-mediated chromatin dynamics sculpt higher-order DNA repair topology

Abstract

Keywords

ASJC Scopus subject areas

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