Volume 23, No 10, Oct 2013

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 23 Issue 10, October 2013: 1215-1228

ORIGINAL ARTICLES

Structure analysis of FAAP24 reveals single-stranded DNA-binding activity and domain functions in DNA damage response

Yucai Wang^2,*, Xiao Han^1,*, Fangming Wu^4,*, Justin W Leung², Megan G Lowery⁵, Huong Do², Junjie Chen², Chaowei Shi⁶, Changlin Tian^4,6, Lei Li^2,3 and Weimin Gong¹

¹Laboratory of Non-coding RNA, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
²Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
³Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
⁴High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, Anhui 230031, China
⁵Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA
⁶National Laboratory for Physical Science at Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230026, China Correspondence: Weimin Gong, E-mail: wgong@ibp.ac.cn; Lei Li, E-mail: leili@mdanerson.org; Changlin Tian(cltian@ustc.edu.cn)

The FANCM/FAAP24 heterodimer has distinct functions in protecting cells from complex DNA lesions such as interstrand crosslinks. These functions rely on the biochemical activity of FANCM/FAAP24 to recognize and bind to damaged DNA or stalled replication forks. However, the DNA-binding activity of this complex was not clearly defined. We investigated how FAAP24 contributes to the DNA-interacting functions of the FANCM/FAAP24 complex by acquiring the N-terminal and C-terminal solution structures of human FAAP24. Modeling of the FAAP24 structure indicates that FAAP24 may possess a high affinity toward single-stranded DNA (ssDNA). Testing of various FAAP24 mutations in vitro and in vivo validated this prediction derived from structural analyses. We found that the DNA-binding and FANCM-interacting functions of FAAP24, although both require the C-terminal (HhH)2 domain, can be distinguished by segregation-of-function mutations. These results demonstrate dual roles of FAAP24 in DNA damage response against crosslinking lesions, one through the formation of FANCM/FAAP24 heterodimer and the other via its ssDNA-binding activity required in optimized checkpoint activation.

10.1038/cr.2013.124

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