MRNIP condensates promote DNA double-strand break sensing and end resection

Yun Long Wang; Wan Wen Zhao; Shao Mei Bai; Li Li Feng; Shu Ying Bie; Li Gong; Fang Wang; Ming Biao Wei; Wei Xing Feng; Xiao Lin Pang; Cao Litao Qin; Xin Ke Yin; Ying Nai Wang; Weihua Zhou; Daniel R. Wahl; Quentin Liu; Ming Chen; Mien Chie Hung; Xiang Bo Wan

doi:10.1038/s41467-022-30303-w

MRNIP condensates promote DNA double-strand break sensing and end resection

Yun Long Wang, Wan Wen Zhao, Shao Mei Bai, Li Li Feng, Shu Ying Bie, Li Gong, Fang Wang, Ming Biao Wei, Wei Xing Feng, Xiao Lin Pang, Cao Litao Qin, Xin Ke Yin, Ying Nai Wang, Weihua Zhou, Daniel R. Wahl, Quentin Liu, Ming Chen, Mien Chie Hung, Xiang Bo Wan

Molecular & Cellular Oncology

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

18 Scopus citations

Abstract

The rapid recognition of DNA double-strand breaks (DSBs) by the MRE11/RAD50/NBS1 (MRN) complex is critical for the initiation of DNA damage response and DSB end resection. Here, we show that MRN complex interacting protein (MRNIP) forms liquid-like condensates to promote homologous recombination-mediated DSB repair. The intrinsically disordered region is essential for MRNIP condensate formation. Mechanically, the MRN complex is compartmentalized and concentrated into MRNIP condensates in the nucleus. After DSB formation, MRNIP condensates move to the damaged DNA rapidly to accelerate the binding of DSB by the concentrated MRN complex, therefore inducing the autophosphorylation of ATM and subsequent activation of DNA damage response signaling. Meanwhile, MRNIP condensates-enhanced MRN complex loading further promotes DSB end resection. In addition, data from xenograft models and clinical samples confirm a correlation between MRNIP and radioresistance. Together, these results reveal an important role of MRNIP phase separation in DSB response and the MRN complex-mediated DSB end resection.

Original language	English (US)
Article number	2638
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-30303-w
State	Published - Dec 2022

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General
General Physics and Astronomy

Access to Document

10.1038/s41467-022-30303-w

Cite this

Wang, Y. L., Zhao, W. W., Bai, S. M., Feng, L. L., Bie, S. Y., Gong, L., Wang, F., Wei, M. B., Feng, W. X., Pang, X. L., Qin, C. L., Yin, X. K., Wang, Y. N., Zhou, W., Wahl, D. R., Liu, Q., Chen, M., Hung, M. C., & Wan, X. B. (2022). MRNIP condensates promote DNA double-strand break sensing and end resection. Nature communications, 13(1), Article 2638. https://doi.org/10.1038/s41467-022-30303-w

@article{60dbffb1b72e4ed48653434d26dfbc8b,

title = "MRNIP condensates promote DNA double-strand break sensing and end resection",

abstract = "The rapid recognition of DNA double-strand breaks (DSBs) by the MRE11/RAD50/NBS1 (MRN) complex is critical for the initiation of DNA damage response and DSB end resection. Here, we show that MRN complex interacting protein (MRNIP) forms liquid-like condensates to promote homologous recombination-mediated DSB repair. The intrinsically disordered region is essential for MRNIP condensate formation. Mechanically, the MRN complex is compartmentalized and concentrated into MRNIP condensates in the nucleus. After DSB formation, MRNIP condensates move to the damaged DNA rapidly to accelerate the binding of DSB by the concentrated MRN complex, therefore inducing the autophosphorylation of ATM and subsequent activation of DNA damage response signaling. Meanwhile, MRNIP condensates-enhanced MRN complex loading further promotes DSB end resection. In addition, data from xenograft models and clinical samples confirm a correlation between MRNIP and radioresistance. Together, these results reveal an important role of MRNIP phase separation in DSB response and the MRN complex-mediated DSB end resection.",

author = "Wang, {Yun Long} and Zhao, {Wan Wen} and Bai, {Shao Mei} and Feng, {Li Li} and Bie, {Shu Ying} and Li Gong and Fang Wang and Wei, {Ming Biao} and Feng, {Wei Xing} and Pang, {Xiao Lin} and Qin, {Cao Litao} and Yin, {Xin Ke} and Wang, {Ying Nai} and Weihua Zhou and Wahl, {Daniel R.} and Quentin Liu and Ming Chen and Hung, {Mien Chie} and Wan, {Xiang Bo}",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-30303-w",

language = "English (US)",

volume = "13",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - MRNIP condensates promote DNA double-strand break sensing and end resection

AU - Wang, Yun Long

AU - Zhao, Wan Wen

AU - Bai, Shao Mei

AU - Feng, Li Li

AU - Bie, Shu Ying

AU - Gong, Li

AU - Wang, Fang

AU - Wei, Ming Biao

AU - Feng, Wei Xing

AU - Pang, Xiao Lin

AU - Qin, Cao Litao

AU - Yin, Xin Ke

AU - Wang, Ying Nai

AU - Zhou, Weihua

AU - Wahl, Daniel R.

AU - Liu, Quentin

AU - Chen, Ming

AU - Hung, Mien Chie

AU - Wan, Xiang Bo

PY - 2022/12

Y1 - 2022/12

N2 - The rapid recognition of DNA double-strand breaks (DSBs) by the MRE11/RAD50/NBS1 (MRN) complex is critical for the initiation of DNA damage response and DSB end resection. Here, we show that MRN complex interacting protein (MRNIP) forms liquid-like condensates to promote homologous recombination-mediated DSB repair. The intrinsically disordered region is essential for MRNIP condensate formation. Mechanically, the MRN complex is compartmentalized and concentrated into MRNIP condensates in the nucleus. After DSB formation, MRNIP condensates move to the damaged DNA rapidly to accelerate the binding of DSB by the concentrated MRN complex, therefore inducing the autophosphorylation of ATM and subsequent activation of DNA damage response signaling. Meanwhile, MRNIP condensates-enhanced MRN complex loading further promotes DSB end resection. In addition, data from xenograft models and clinical samples confirm a correlation between MRNIP and radioresistance. Together, these results reveal an important role of MRNIP phase separation in DSB response and the MRN complex-mediated DSB end resection.

AB - The rapid recognition of DNA double-strand breaks (DSBs) by the MRE11/RAD50/NBS1 (MRN) complex is critical for the initiation of DNA damage response and DSB end resection. Here, we show that MRN complex interacting protein (MRNIP) forms liquid-like condensates to promote homologous recombination-mediated DSB repair. The intrinsically disordered region is essential for MRNIP condensate formation. Mechanically, the MRN complex is compartmentalized and concentrated into MRNIP condensates in the nucleus. After DSB formation, MRNIP condensates move to the damaged DNA rapidly to accelerate the binding of DSB by the concentrated MRN complex, therefore inducing the autophosphorylation of ATM and subsequent activation of DNA damage response signaling. Meanwhile, MRNIP condensates-enhanced MRN complex loading further promotes DSB end resection. In addition, data from xenograft models and clinical samples confirm a correlation between MRNIP and radioresistance. Together, these results reveal an important role of MRNIP phase separation in DSB response and the MRN complex-mediated DSB end resection.

UR - http://www.scopus.com/inward/record.url?scp=85130638263&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85130638263&partnerID=8YFLogxK

U2 - 10.1038/s41467-022-30303-w

DO - 10.1038/s41467-022-30303-w

M3 - Article

C2 - 35551189

AN - SCOPUS:85130638263

SN - 2041-1723

VL - 13

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 2638

ER -

MRNIP condensates promote DNA double-strand break sensing and end resection

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this