Inducing DNA damage through R-loops to kill cancer cells

Fred C Lam; Yi Wen Kong; Michael B Yaffe

doi:10.1080/23723556.2020.1848233

Inducing DNA damage through R-loops to kill cancer cells

Mol Cell Oncol. 2020 Nov 20;8(1):1848233. doi: 10.1080/23723556.2020.1848233.

Authors

Fred C Lam^{1

2

3

4}, Yi Wen Kong^{2

3

4}, Michael B Yaffe^{2

3

4

5}

Affiliations

¹ Division of Neurosurgery, Hamilton General Hospital, McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada.
² Center for Precision Cancer Medicine at MIT, Cambridge, MA, USA.
³ Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA, USA.
⁴ Departments of Biology and Bioengineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁵ Beth Israel Deaconess Medical Center, Department of Surgery, Harvard Medical School, Boston, MA, USA.

Abstract

R-loops are intermediate structures of transcription that can accumulate when transcriptional elongation is blocked by inhibiting BRD4. In normal cells, R-loop persistence suppresses firing of adjacent replication origins. This control is lost in a subset of cancer cells, where BRD4 inhibition results in R-loop accumulation, leading to transcription-replication collisions and DNA double-strand breaks during S-phase, followed by cell death. This finding sheds new light on the mechanisms by which BRD4 inhibitors function as cancer therapies, and indicates that targeting other cellular events to cause R-loop accumulation may be useful for cancer treatment.

Keywords: BRD4; DNA damage; R-loops; bromodomain proteins; replication stress; transcription-replication conflicts.

Abstract

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