Lilian Kabeche, PhD
Assistant ProfessorCards
About
Research
Overview
The Kabeche lab strives 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 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 component of the centromere and mitotic machinery that ensures faithful chromosome segregation. Our previous work demonstrated that during mitosis, ATR acts independent of its function as part of the DNA damage response pathway and helps promote the activity of a major mitotic kinase: Aurora B. We continue to further study how ATR is activated, regulated and fully elucidate the mechanism by which ATR regulates mitotic processes to ensure that cells segregate their chromosomes faithfully.
In addition to studying ATR, we have also made exciting discoveries on novel functions of other components of the DDR pathway in mitosis.
Area 2: Investigating non-canonical roles of DNA damage repair proteins in interphase.
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. Through our studies we discovered that ATR promotes genome stability by maintaining centromere identity through its regulation of histone chaperones, including DAXX. Loss of ATR, even in the absence of DNA damage led to an inappropriate deposition of H3.3 histones and loss of CENP-A histones at centromeres, leading a loss of centromere identity. This work has opened up many questions of the mechanism by which ATR regulates DAXX and other histone chaperones and how ATR is regulated in the absence of DNA damage. We aim to study this to further understand how healthy and cancer cells are affected by ATR inhibitors, which are currently being tested in the clinic.
Links & Media
News
- May 17, 2023Source: Yale West Campus
Multi-tasking protein has potential to protect against disease
- May 19, 2021Source: Yale West Campus
Two Yale Scientists Receive the Pershing Square Sohn Prize for Young Investigators in Cancer Research
- May 18, 2021
Two Yale Cancer Center scientists awarded the Pershing Square Sohn Prize for Young Investigators in Cancer Research