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) a DNA/RNA dual-activity topoisomerase complex that regulates DNA transcription, mRNA translation, neurodevelopment and mental health disorders (including autism and schizophrenia), stress tolerance, and lifespan maintenance; (2) proteins and their associated complexes involved in mental health disorders, neurodegeneration, genome instability diseases, and the DNA damage response; and (3) chromatin-remodeling complexes that regulate transcription, replication and repair. 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. Many of these processes affect life span, and their defects are linked to mental health disorders, age-associated neurodegeneration and genome instability syndromes, and cancer. The team 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 complexes. 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 mRNA, and to prevent mental health disorders and maintain normal lifespan.

List of Portfolio/Research Areas

The GICRS works in three main research areas:

  • A DNA/RNA dual-activity topoisomerase complex that regulates DNA transcription, mRNA translation, mental health disorders, stress tolerance, and lifespan maintenance.
  • Proteins and their associated complexes involved in mental health disorders, neurodegeneration, genome instability diseases, and the DNA damage response
  • 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.