Structure of DNMT3B homo-oligomer reveals vulnerability to impairment by ICF mutations

Linfeng Gao, Yiran Guo, Mahamaya Biswal, Jiuwei Lu, Jiekai Yin, Jian Fang, Xinyi Chen, Zengyu Shao, Mengjiang Huang, Yinsheng Wang, Gang Greg Wang () and Jikui Song ()
Additional contact information
Linfeng Gao: University of California
Yiran Guo: University of North Carolina at Chapel Hill School of Medicine
Mahamaya Biswal: University of California
Jiuwei Lu: University of California
Jiekai Yin: University of California
Jian Fang: University of California
Xinyi Chen: University of California
Zengyu Shao: University of California
Mengjiang Huang: University of California
Yinsheng Wang: University of California
Gang Greg Wang: University of North Carolina at Chapel Hill School of Medicine
Jikui Song: University of California

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract DNA methyltransferase DNMT3B plays an essential role in establishment of DNA methylation during embryogenesis. Mutations of DNMT3B are associated with human diseases, notably the immunodeficiency, centromeric instability and facial anomalies (ICF) syndrome. How ICF mutations affect DNMT3B activity is not fully understood. Here we report the homo-oligomeric structure of DNMT3B methyltransferase domain, providing insight into DNMT3B-mediated DNA methylation in embryonic stem cells where the functional regulator DNMT3L is dispensable. The interplay between one of the oligomer interfaces (FF interface) and the catalytic loop renders DNMT3B homo-oligomer a conformation and activity distinct from the DNMT3B-DNMT3L heterotetramer, and a greater vulnerability to certain ICF mutations. Biochemical and cellular analyses further reveal that the ICF mutations of FF interface impair the DNA binding and heterochromatin targeting of DNMT3B, leading to reduced DNA methylation in cells. Together, this study provides a mechanistic understanding of DNMT3B-mediated DNA methylation and its dysregulation in disease.

Date: 2022
References: View references in EconPapers View complete reference list from CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/s41467-022-31933-w Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31933-w

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-31933-w

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().