What we care about
What we investigate
We strive to understand the interplay between chromosomal instability (CIN) and DNA damage response (DDR) defects in cancers and develop new strategies to target CIN in cancer therapy. Chromosomal instability (CIN) is hallmark of cancer whereby cells continuously gain and/or lose whole chromosomes. CIN is present in over 90% of solid tumors and 50% hematopoietic cancers and is correlated with immune evasion, drug resistance, and increased metastasis and poor patient prognosis. CIN itself is self-propagating and can lead to increased genomic instability, whereby chromosome missegregation events can lead to DNA damage during interphase. DNA damage in turn can cause chromosome missegregation creating further genomic instability upon missegregation events. Therefore, it is necessary to understand how the DDR pathway and the mitotic machinery work together and independently to promote genome stability. We have two major areas of research:
Area 1: Investigating the role of the DNA damage repair pathway in mitosis.
A major focus in the lab is on Ataxia telangiectasia and Rad3 related (ATR) kinase, a master regulator of the DDR pathway. ATR is an important component of the centromere and mitotic machinery that ensures faithful chromosome segregation. During mitosis, centromere transcription continues and the RNA product can loop back to create an RNA:DNA hybrid, or R-loop. ATR is recruited to centromeres in the presence of R-loops, where it promotes faithful chromosome segregation by activating Aurora B, a major mitotic kinase. Importantly, this new role for ATR, discovered during my postdoctoral work, is DNA damage independent, leading to many new questions. We are currently studying the mechanism by which other DDR proteins promote faithful mitotic progression and further understanding the role of ATR in mitosis.
Area 2: Investigate the role of R-loops in maintaining proper centromere identity.
We are also interested in understanding how R-loops promote proper chromosome segregation. It is known that CENP-A loading onto centromeres occurs at the end of mitosis and into G1. Centromeres are replicated with the rest of the genome in S phase and CENP-A is re-deposited at centromeres again in G2. Interestingly, these processes depend on proper centromeric transcription by RNA Polymerase II. Transcription of centromeric regions leads to the formation to R-loop formation in mitosis. We are exploring these mechanisms by determining the cell cycle timing of centromeric R-loops and investigate the mechanism by which R-loops promote centromere loading in G2.