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The histone methyltransferase DOT1L is required for DNA damage recognition and repair

Sanjay Kumar Raul
Doctoral thesis
Date of Examination: 2016-12-20
Date of issue: 2017-02-02
Advisor: Johnsen, Steven A. Prof. Dr.
Referee: Meyer, Thomas Prof. Dr.
Referee: Zeisberg, Michael Prof. Dr.

Persistent Address: http://hdl.handle.net/11858/00-1735-0000-002B-7D2D-A

 

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Abstract

English

New effective combinational therapeutic strategies are an alternative choice for a successful translational study. Disruptor of telomeric silencing 1-like (DOT1L) is a histone 3 lysine 79 (H3K79) methyltransferase enzyme and its inhibition is being tested in phase 1 clinical trials. DOT1L has been implicated in many biological functions ranging from cell cycle regulation, transcriptional regulation, and heterochromatin formation, however, the functions of DOT1L in DNA-damage response remains to be unraveled. DNA double-strand breaks (DSB) are one of the most lethal forms of DNA damage and can lead to several disease phenotypes, including cancer. In this study, we investigated the role of DOT1L in the DNA double-strand break repair-pathway. Our results indicate that DOT1L is required for proper DNA-damage response and repair of DNA DSBs via a homologous recombination (HR) pathway. DOT1L activity prevents the proliferation of cancer cells; therefore this is a potential future cancer therapeutic target. And more importantly, our results show the combination of small molecule inhibitor PARP with other available chemotherapeutics agents shows synergism in the colorectal cancer cells. The data further suggest DOT1L plays a role HR-mediated DNA double strand break and loss of DOT1L functions leads to increased sensitivity to PARP inhibition. Therefore, we hypothesize that DOT1L activity (i.e. H3K79me3) may serve as a marker for molecular stratification of colorectal cancer.
Keywords: DOT1L; DNA repair; PARP
Schlagwörter: Molecular Medicine
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