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) a dual-activity topoisomerase complex and its roles in DNA transcription, mRNA metabolism, coronavirus RNA replication, 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 and viral RNA replication. Because defects in these processes can reduce life span and trigger genome instability syndromes and cancer, the Section investigates how DNA- and RNA-remodeling complexes influence normal aging and prevent 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 topoisomerase complex. Given that Top3b is the first dual-activity 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 cellular and viral 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 a dual-activity topoisomerase complex in DNA transcription, mRNA and viral RNA metabolism, neuronal development and life-span regulation. We are currently examining whether the complex can regulate coronavirus RNA replication, so that it can be a drug target for COVID-19. .
- Chromatin-remodeling complexes that regulate transcription, replication and repair.
Findings and Publications
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.
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.
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.
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
Joo Y, Xue Y, Wang Y, McDevitt RA, Sah N, Bossi S, Su S, Lee SK, Peng W, Xie A, Zhang Y, Ding Y, Ku WL, Ghosh S, Fishbein K, Shen W, Spencer R, Becker K, Zhao K, Mattson MP, van Praag H, Sharov A, Wang W. Topoisomerase 3β knockout mice show transcriptional and behavioural impairments associated with neurogenesis and synaptic plasticity. Nat Commun. 2020;11(1):3143.