Genome Instability and Chromatin Remodeling Section
Weidong Wang, PhD, Chief
The Genome Instability and Chromatin Remodeling Section (GICRS), led by Weidong Wang, focuses on three main projects: (1) multiprotein complexes in DNA damage response and genome maintenance, (2) RNA topoisomerases and their roles in RNA metabolism, neurodevelopment and mental disorders, and (3) chromatin remodeling complexes and gene regulation. The Section has a strong interest in nucleic acid remodeling complexes that play essential roles in DNA transcription, replication, and repair, as well as in mRNA translation. Because many of these processes affect life span, and their defects can cause age-related disorders, genome instability syndromes, and cancer, the Section investigates if DNA and RNA remodeling complexes play crucial roles in maintaining normal aging and preventing premature aging disorders. The team uses biochemical approaches to define targeted nucleic acid-remodeling complexes from cell extracts of mammals and fruit flies. The GICRS has successfully identified components of the Fanconi anemia core complex, Bloom syndrome complex, ATRX-syndrome complex, FANCM-MHF DNA remodeling complex, RNF8-FAAP20 ubiquitin cascade, several chromatin-remodeling complexes (BAF, PBAF, NURD), and Top3b-TDRD3 RNA topoisomerase complex. Given that Top3b is the first RNA topoisomerase identified in eukaryotes, the group is working to elucidate how it functions with its partners, TDRD3 and FMRP (Fragile X syndrome proteins), to solve topological problems in RNA metabolism.
List of Portfolio/Research Areas
The GICRS works in three main research areas:
- Multiprotein complexes involved in genome instability diseases and the DNA damage response.
- The roles of RNA topoisomerases in RNA metabolism and an RNA topoisomerase complex that works with the Fragile X syndrome protein (FMRP) to promote neuronal development and prevent mental dysfunction.
- Chromatin-remodeling complexes that regulate transcription, replication and repair.
Findings and Publications
Yan Z, Guo R, Paramasivam M, Shen W, Ling C, Fox D 3rd, Wang Y, Oostra AB, Kuehl J, Lee DY, Takata M, Hoatlin ME, Schindler D, Joenje H, de Winter JP, Li L, Seidman MM, Wang W. A ubiquitin-binding protein, FAAP20, links RNF8-mediated ubiquitination to the Fanconi anemia DNA repair network. Mol Cell. 47(1):61-75, 2012.
Yan Z, Delannoy M, Ling C, Daee D, Osman F, Muniandy PA, Shen X, Oostra AB, Du H,et al. A histone-fold complex and FANCM form a conserved DNA-remodeling complex to maintain genome stability. Mol Cell. 37(6):865-78, 2010.
Lee SK, Xue Y, Shen W, Zhang Y, Joo Y, Ahmad M, Chinen M, Ding Y, Ku WL, De S, Lehrmann E, Becker KG, Lei EP, Zhao K, Zou S, Sharov A, Wang W. Topoisomerase 3β interacts with RNAi machinery to promote heterochromatin formation and transcriptional silencing in Drosophila. Nat Commun. 2018 Nov 23;9(1):4946. doi: 10.1038/s41467-018-07101-4. PMID:30470739
Xu D, Shen W, Guo R, Xue Y, Peng W, Sima J, Yang J, Sharov A, Srikantan S, Yang J, Fox D 3rd, et. al. Top3β is an RNA topoisomerase that works with fragile X syndrome protein to promote synapse formation. Nat Neurosci. 16(9):1238-47, 2013.
Ahmad M, Shen W, Li W, Xue Y, Zou S, Xu D, Wang W. Topoisomerase 3β is the major topoisomerase for mRNAs and linked to neurodevelopment and mental dysfunction. Nucleic Acids Res. Dec 29. doi: 10.1093/nar/gkw1293, 2016.