The TONSL-MMS22L complex and FANCM form an interdependent complex on chromatin to counter replication stress

  • bioRxiv. 2025 Mar 10:2025.03.07.642025. doi: 10.1101/2025.03.07.642025.
Haixia Zhou  1  2 ,  Jiaoyan Yan  1  3  2 ,  Xinlei Cao  1  3  2 ,  Jingfei Zhan  3  2 ,  Chen Ling  4  5 ,  Yunhui Luo  3 ,  Zhuang Ma  3 ,  Yinyying Sun  3 ,  Peining Song  3 ,  Weiwei Liu  3 ,  Lizhu Wang  3 ,  Jiahuan Li  1  3 ,  Althaf Shaik  5 ,  Marina Bellani  5 ,  Linqian Wang  1  3 ,  Yun Xie  1  3 ,  Jing Zhang  5  6 ,  Xiangyang Xue  1  3  7 ,  Xian Shen  7 ,  Michael M Seidman  5 ,  Weidong Wang  4 ,  Zhijiang Yan  1  3  4  8
Affiliations
  • 1. Oncology Discipline Group, The Key Laboratory of Pediatric Hematology and oncology Diseases of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, China.
  • 2. These authors contributed equally.
  • 3. Institute of DNA Repair Diseases, School of Basic Medical Sciences, Wenzhou Medical University, China.
  • 4. Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, USA.
  • 5. Laboratory of Molecular Biology & Immunology, National Institute on Aging, National Institutes of Health, USA.
  • 6. Tongji University School of Medicine, China.
  • 7. Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
  • 8. Lead Contact.
PMID: 41030968 DOI: 10.1101/2025.03.07.642025
Abstract

FANCM is branchpoint DNA translocase essential for cellular response to replication stress. Here, we show that replication stress stimulates FANCM and the TONSL-MMS22L heterodimer bound to histones H3-H4 to form an interdependent complex on chromatin. TONSL-MMS22L recruits FANCM and Fanconi anemia (FA) core complex to stalled and collapsed forks, maintains FANCM on replication-stressed chromatin, promotes FANCD2 monoubiquitination, facilitates both repair and replication traverse of DNA interstrand crosslinks (ICLs), and suppresses sister chromatid exchanges, through its interactions with FANCM and H3-H4. Reciprocally, both DNA translocase activity and phosphorylation of FANCM facilitate recruitment of TONSL-MMS22L and RAD51 to perturbed forks. Moreover, TONSL-MMS22L and FANCM function together to promote activation of the FA pathway, ICL repair, homologous recombination and replication traverse. Cancer patients with tumors with wildtype FANCM and low expression of TONSL-MMS22L have a more favorable prognosis than those with high expression. Thus, FANCM-TONSL-MMS22L acts coordinately as a complex on chromatin that resolves replication stress, and this complex may present a therapeutic target for wildtype FANCM-linked Cancer.

Keywords
FANCM; Fanconi Anemia; TONSL-MMS22L; replication stress.
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