RIF1-ASF1-mediated high-order chromatin structure safeguards genome integrity

Sumin Feng; Sai Ma; Kejiao Li; Shengxian Gao; Shaokai Ning; Jinfeng Shang; Ruiyuan Guo; Yingying Chen; Britny Blumenfeld; Itamar Simon; Qing Li; Rong Guo; Dongyi Xu

doi:10.1038/s41467-022-28588-y

RIF1-ASF1-mediated high-order chromatin structure safeguards genome integrity

Sumin Feng, Sai Ma, Kejiao Li, Shengxian Gao, Shaokai Ning, Jinfeng Shang, Ruiyuan Guo, Yingying Chen, Britny Blumenfeld, Itamar Simon, Qing Li, Rong Guo, Dongyi Xu^*

^*Corresponding author for this work

Department of Microbiology and Molecular Genetics

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

2 Scopus citations

Abstract

The 53BP1-RIF1 pathway antagonizes resection of DNA broken ends and confers PARP inhibitor sensitivity on BRCA1-mutated tumors. However, it is unclear how this pathway suppresses initiation of resection. Here, we identify ASF1 as a partner of RIF1 via an interacting manner similar to its interactions with histone chaperones CAF-1 and HIRA. ASF1 is recruited to distal chromatin flanking DNA breaks by 53BP1-RIF1 and promotes non-homologous end joining (NHEJ) using its histone chaperone activity. Epistasis analysis shows that ASF1 acts in the same NHEJ pathway as RIF1, but via a parallel pathway with the shieldin complex, which suppresses resection after initiation. Moreover, defects in end resection and homologous recombination (HR) in BRCA1-deficient cells are largely suppressed by ASF1 deficiency. Mechanistically, ASF1 compacts adjacent chromatin by heterochromatinization to protect broken DNA ends from BRCA1-mediated resection. Taken together, our findings identify a RIF1-ASF1 histone chaperone complex that promotes changes in high-order chromatin structure to stimulate the NHEJ pathway for DSB repair.

Original language	American English
Article number	957
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-28588-y
State	Published - Dec 2022

Bibliographical note

Funding Information:
We thank Weidong Wang for his advice and revisions to the manuscript. We thank the Analytical Instrumentation Center in Peking University, the Imaging Core and Mass-spectrum Core at the National Center for Protein Sciences at Peking University for imaging and mass-spectrum analysis. U2OS-265 cells were a gift from Daniel Durocher under a permission of Roger A. Greenberg. This work was supported in part by Beijing Outstanding Young Scientist Program (BJJWZYJH01201910001005) to Q.L., the National Key Research and Development Program of China (2021YFA0909304) to D.X., and the National Natural Science Foundation of China (31870807 and 32071285 to R.G., and 82002991 to S.F.).

Publisher Copyright:
© 2022, The Author(s).

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10.1038/s41467-022-28588-y

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@article{dc21dd52ca7049c1881b3be310938b01,

title = "RIF1-ASF1-mediated high-order chromatin structure safeguards genome integrity",

abstract = "The 53BP1-RIF1 pathway antagonizes resection of DNA broken ends and confers PARP inhibitor sensitivity on BRCA1-mutated tumors. However, it is unclear how this pathway suppresses initiation of resection. Here, we identify ASF1 as a partner of RIF1 via an interacting manner similar to its interactions with histone chaperones CAF-1 and HIRA. ASF1 is recruited to distal chromatin flanking DNA breaks by 53BP1-RIF1 and promotes non-homologous end joining (NHEJ) using its histone chaperone activity. Epistasis analysis shows that ASF1 acts in the same NHEJ pathway as RIF1, but via a parallel pathway with the shieldin complex, which suppresses resection after initiation. Moreover, defects in end resection and homologous recombination (HR) in BRCA1-deficient cells are largely suppressed by ASF1 deficiency. Mechanistically, ASF1 compacts adjacent chromatin by heterochromatinization to protect broken DNA ends from BRCA1-mediated resection. Taken together, our findings identify a RIF1-ASF1 histone chaperone complex that promotes changes in high-order chromatin structure to stimulate the NHEJ pathway for DSB repair.",

author = "Sumin Feng and Sai Ma and Kejiao Li and Shengxian Gao and Shaokai Ning and Jinfeng Shang and Ruiyuan Guo and Yingying Chen and Britny Blumenfeld and Itamar Simon and Qing Li and Rong Guo and Dongyi Xu",

note = "Funding Information: We thank Weidong Wang for his advice and revisions to the manuscript. We thank the Analytical Instrumentation Center in Peking University, the Imaging Core and Mass-spectrum Core at the National Center for Protein Sciences at Peking University for imaging and mass-spectrum analysis. U2OS-265 cells were a gift from Daniel Durocher under a permission of Roger A. Greenberg. This work was supported in part by Beijing Outstanding Young Scientist Program (BJJWZYJH01201910001005) to Q.L., the National Key Research and Development Program of China (2021YFA0909304) to D.X., and the National Natural Science Foundation of China (31870807 and 32071285 to R.G., and 82002991 to S.F.). Publisher Copyright: {\textcopyright} 2022, The Author(s).",

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AU - Feng, Sumin

AU - Ma, Sai

AU - Li, Kejiao

AU - Gao, Shengxian

AU - Ning, Shaokai

AU - Shang, Jinfeng

AU - Guo, Ruiyuan

AU - Chen, Yingying

AU - Blumenfeld, Britny

AU - Simon, Itamar

AU - Li, Qing

AU - Guo, Rong

AU - Xu, Dongyi

N1 - Funding Information: We thank Weidong Wang for his advice and revisions to the manuscript. We thank the Analytical Instrumentation Center in Peking University, the Imaging Core and Mass-spectrum Core at the National Center for Protein Sciences at Peking University for imaging and mass-spectrum analysis. U2OS-265 cells were a gift from Daniel Durocher under a permission of Roger A. Greenberg. This work was supported in part by Beijing Outstanding Young Scientist Program (BJJWZYJH01201910001005) to Q.L., the National Key Research and Development Program of China (2021YFA0909304) to D.X., and the National Natural Science Foundation of China (31870807 and 32071285 to R.G., and 82002991 to S.F.). Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - The 53BP1-RIF1 pathway antagonizes resection of DNA broken ends and confers PARP inhibitor sensitivity on BRCA1-mutated tumors. However, it is unclear how this pathway suppresses initiation of resection. Here, we identify ASF1 as a partner of RIF1 via an interacting manner similar to its interactions with histone chaperones CAF-1 and HIRA. ASF1 is recruited to distal chromatin flanking DNA breaks by 53BP1-RIF1 and promotes non-homologous end joining (NHEJ) using its histone chaperone activity. Epistasis analysis shows that ASF1 acts in the same NHEJ pathway as RIF1, but via a parallel pathway with the shieldin complex, which suppresses resection after initiation. Moreover, defects in end resection and homologous recombination (HR) in BRCA1-deficient cells are largely suppressed by ASF1 deficiency. Mechanistically, ASF1 compacts adjacent chromatin by heterochromatinization to protect broken DNA ends from BRCA1-mediated resection. Taken together, our findings identify a RIF1-ASF1 histone chaperone complex that promotes changes in high-order chromatin structure to stimulate the NHEJ pathway for DSB repair.

AB - The 53BP1-RIF1 pathway antagonizes resection of DNA broken ends and confers PARP inhibitor sensitivity on BRCA1-mutated tumors. However, it is unclear how this pathway suppresses initiation of resection. Here, we identify ASF1 as a partner of RIF1 via an interacting manner similar to its interactions with histone chaperones CAF-1 and HIRA. ASF1 is recruited to distal chromatin flanking DNA breaks by 53BP1-RIF1 and promotes non-homologous end joining (NHEJ) using its histone chaperone activity. Epistasis analysis shows that ASF1 acts in the same NHEJ pathway as RIF1, but via a parallel pathway with the shieldin complex, which suppresses resection after initiation. Moreover, defects in end resection and homologous recombination (HR) in BRCA1-deficient cells are largely suppressed by ASF1 deficiency. Mechanistically, ASF1 compacts adjacent chromatin by heterochromatinization to protect broken DNA ends from BRCA1-mediated resection. Taken together, our findings identify a RIF1-ASF1 histone chaperone complex that promotes changes in high-order chromatin structure to stimulate the NHEJ pathway for DSB repair.

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DO - 10.1038/s41467-022-28588-y

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JO - Nature Communications

JF - Nature Communications

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ER -

RIF1-ASF1-mediated high-order chromatin structure safeguards genome integrity

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