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The Relationship Between DOT1L, Histone H3 Methylation, and Genome Stability in Cancer

  • Epigenetics (J Davie and C Nelson, Section Editors)
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Abstract

Purpose of Review

This review describes how disruptor of telomeric silencing 1-like (DOT1L) and histone H3 at lysine 79 (H3K79) methylation maintain genome stability under normal conditions and discusses the consequences of their dysregulation. We highlight the roles that DOT1L and H3K79 methylation have in various cellular processes and detail their roles in the DNA damage response and mitotic fidelity.

Recent Findings

DOT1L is currently the only known enzyme capable of catalyzing the methylation of H3K79. DOT1L activity and H3K79 methylation regulate a number of key cellular processes required to maintain genome stability, including transcription, cell cycle progression, and the DNA damage response. Consequently, alterations of DOT1L activity and H3K79 methylation patterning are predicted to compromise genome stability.

Summary

Consistent with a putative role in oncogenesis, aberrant DOT1L expression and function occur in a wide range of cancer types including breast, colorectal, and lung, yet the exact mechanisms linking altered DOT1L expression and H3K79 methylation to genome instability remain poorly understood.

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Acknowledgements

We thank members of the McManus lab for helpful suggestions. We are grateful for operational support from CIHR (KJM; MOP 115179) CancerCare Manitoba (KJM). BJG is a recipient of a University of Manitoba GETS award, while LMPJ is a recipient of a Research Manitoba/CancerCare Manitoba Foundation studentship. We acknowledge the strong support of the Research Institute in Oncology and Hematology and the CancerCare Manitoba Foundation.

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Authors and Affiliations

  1. Department of Biochemistry & Medical Genetics, University of Manitoba, Winnipeg, MB, Canada

    Brent J. Guppy, Lucile M-P. Jeusset & Kirk J. McManus

  2. Research Institute in Oncology and Hematology, CancerCare Manitoba, ON6010 - 675 McDermot Avenue, Winnipeg, MB, R3E 0V9, Canada

    Brent J. Guppy, Lucile M-P. Jeusset & Kirk J. McManus

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  1. Brent J. Guppy
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Correspondence to Kirk J. McManus.

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Brent J. Guppy, Lucile M-P. Jeusset, and Kirk J. McManus each declare that they have no conflicts of interest.

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Guppy, B.J., Jeusset, L.MP. & McManus, K.J. The Relationship Between DOT1L, Histone H3 Methylation, and Genome Stability in Cancer. Curr Mol Bio Rep 3, 18–27 (2017). https://doi.org/10.1007/s40610-017-0051-0

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