What we investigate

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 mis-segregation 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: How do the proteins of the DNA damage response pathway promote proper mitotic progression.

A major focus in the lab is investigating how components of the DNA damage response pathway work in mitosis outside of their canonical functions of repairing DNA. We have focused much of our time investigating the role of Ataxia telangiectasia and Rad3 related (ATR) kinase, a master regulator of the DDR pathway. Our previous work demonstrated that ATR is an important centromere and mitotic machinery component that ensures faithful chromosome segregation. Our previous work demonstrated that  ATR acts independent of its function during mitosis as part of the DNA damage response pathway and helps promote the activity of a major mitotic kinase: Aurora B. We continue to study how ATR activity is regulated in mitosis and how ATR regulates mitotic progression. We have also expanded beyond ATR to look at ATM, Chk1, and Chk2. We find that these DDR kinases are on and have vastly distinct roles and interactors in mitosis than they do in interphase.

Area 2: How do cells maintain proper centromere identity?

A second major focus in the lab is investigating how components of the DNA damage response pathway work outside of their function as part of the DNA damage response pathway to promote genome stability by regulating centromere identity. Centromeres act as the base for the kinetochore, a multi-protein structure that links chromosomes to mitotic spindles. Thus, their regulation is necessary for proper chromosome segregation. Centromeres are a region of the chromosome marked by the presence of CENP-A, an H3 histone variant. Through our studies, we discovered that ATR promotes genome stability by maintaining centromere identity by regulating histone chaperones, including DAXX. This work has opened up many questions about the mechanism by which ATR regulates DAXX and other histone chaperones, the dynamics of CENP-A loading and eviction, and how centromere identity is maintained in cancer cells that experience DNA damage.