Tang Lab

The Tang laboratory applies a wide range of approaches such as live-cell imaging, single-cell genomics, and biochemistry to study the mechanisms of complex genome rearrangements in cancers, developmental disorders, and other human diseases.

Genome instability, characterized by both DNA mutations and chromosomal rearrangements, is a hallmark of cancer. In contrast to classical models that propose these mutational processes occur gradually, recent studies have identified catastrophic mutational phenomenon that extensively alter the genome “all-at-once”. One such process is termed chromothripsis. Chromothripsis is characterized by massive chromosomal rearrangements on one or a few chromosomes within a single cell cycle. Comprehensive genomic analysis indicates that chromothripsis is prevalent across cancer types and can cause human developmental disorders.

Chromothripsis was recently shown to occur in abnormal nuclear structures called micronuclei, but how DNA contained in micronuclei underwent breakage remained unknown. We demonstrated that aberrant processing of transcriptional intermediates in micronuclei leads to DNA break formation in micronuclei, and likely contributes to chromothripsis. We continue to be interested in dissecting the molecular mechanism of how DNA breaks are formed in micronuclei, how they are processed, and their contribution to genome instability.

We are also more broadly interested in DNA damage from transcriptional intermediates. R-loops, composed of DNA paired with RNA as well as a displaced DNA strand, have been shown to be involved in many important physiological functions, including regulating transcription, immunoglobulin genes rearrangement, mitochondria DNA replication. However, the aberrant accumulation of R-loops can also lead to DNA damage and genome instability. Therefore, another interest of the lab is to study the regulation of R-loop formation, resolution, and its function in different cellular contexts, particularly focused on the roles of R-loops in DNA damage and repair in somatic and meiotic cells.

Tang S, Stokasimov E, Cui Y, Pellman D. Breakage of cytoplasmic chromosomes by pathological DNA base excision repair. Nature 2022, 606, 930-936.

Tang S., Wu K.Y.M., Zhang R. Hunter N. (2015). Pervasive and essential roles of the Top3-Rmi1 decatenase orchestrate recombination and facilitate chromosome segregation in meiosis. Molecular Cell 57, 607-21.

Copsey, A., Tang, S*. Jordan, P., Blitzblau, H., Newcombe, S., Lambacher, N. Chan, A.C., Newnham, L., Li, Z., Arumugam, P., Hochwagen, A., Neil Hunter, N., Hoffmann, E. (2013). Smc5/6 coordinates formation and resolution of joint molecules with chromosome morphology to ensure meiotic divisions. PLoS Genetics 9, e1004071, doi: 10.1371/journal.pgen.1004071. *joint first author.

Zakharyevich, K., Tang, S., Ma, Y., and Hunter, N. (2012). Delineation of joint molecule resolution pathways in meiosis identifies a crossover-specific resolvase. Cell 149, 334-347.

Zakharyevich K, Ma Y, Tang S, Hwang PY, Boiteux S, Hunter N. (2010). Temporally and biochemically distinct activities of Exo1 during meiosis: double-strand break resection and resolution of double Holliday junctions. Molecular Cell 40, 1001-15.