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New insight into DNA repair

Date:
August 3, 2015
Source:
University of Texas M. D. Anderson Cancer Center
Summary:
DNA double-strand breaks (DSBs) are the worst possible form of genetic malfunction that can cause cancer and resistance to therapy, scientists have found. New research reveals more about why this occurs and how these breaks can be repaired.
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DNA double-strand breaks (DSBs) are the worst possible form of genetic malfunction that can cause cancer and resistance to therapy. New information published reveals more about why this occurs and how these breaks can be repaired.

Scientists at The University of Texas MD Anderson Cancer Center reported their findings about the role of the enzyme fumarase in DNA repair in the Aug. 3, 2015 issue of Nature Cell Biology.

"Our study showed that the enzymatic activity of the metabolic enzyme fumarase and its product, fumarate, are critical elements of the DNA damage response and that fumarase deficiency promotes tumor growth due to impairment of DNA repair," said Zhimin Lu, M.D., Ph.D., professor of Neuro-Oncology.

Lu's team demonstrated that fumarase accomplishes this through a process critical for gene regulation and expression known as histone methylation. Many cancers are thought to result from misregulated histone methylation.

Another crucial component of the DNA repair process is DNA-PK, a protein kinase that governs DNA damage response, helping to assure genetic stability. The researchers defined how DNA-PK and fumarase interact to increase histone methylation, allowing for DNA repair and restoration of healthy cells.

"We know that histone methylation regulates DNA repair, but the mechanisms underlying this repair has not been fully understood," he said. "Our research revealed a 'feedback' mechanism that underlies DNA-PK regulation by chromatin-associated fumarase and the function of this fumarase in regulating histone methylation and DNA repair."

This chain-of-event repair process occurs at the DSB regions and initiates a DNA damage "fix" by joining the tail ends of the double strand breaks.

Increasingly, inhibition of DNA-PKs and fumarase are being looked at for its potential to sensitize cancer cells to chemotherapy or radiotherapy. It is hoped a more thorough understanding about how they accomplish this can lead to new approaches to cancer treatment.

Dr. Lu's group previously reported that another metabolic enzyme, pyruvate kinase M2 (PKM2) acts as a protein kinase in regulation of the Warburg effect, a process by which cancer cells produce energy, as well for regulation of gene expression and cell cycle progression.

"Our new findings on fumarase's role in DNA repair further demonstrate that metabolic enzymes can possess non-metabolic functions in crucial cellular activities of cancer cells," said Lu.


Story Source:

Materials provided by University of Texas M. D. Anderson Cancer Center. Note: Content may be edited for style and length.


Journal Reference:

  1. Yuhui Jiang, Xu Qian, Jianfeng Shen, Yugang Wang, Xinjian Li, Rui Liu, Yan Xia, Qianming Chen, Guang Peng, Shiaw-Yih Lin, Zhimin Lu. Local generation of fumarate promotes DNA repair through inhibition of histone H3 demethylation. Nature Cell Biology, 2015; DOI: 10.1038/ncb3209

Cite This Page:

University of Texas M. D. Anderson Cancer Center. "New insight into DNA repair." ScienceDaily. ScienceDaily, 3 August 2015. <www.sciencedaily.com/releases/2015/08/150803111217.htm>.
University of Texas M. D. Anderson Cancer Center. (2015, August 3). New insight into DNA repair. ScienceDaily. Retrieved May 23, 2017 from www.sciencedaily.com/releases/2015/08/150803111217.htm
University of Texas M. D. Anderson Cancer Center. "New insight into DNA repair." ScienceDaily. www.sciencedaily.com/releases/2015/08/150803111217.htm (accessed May 23, 2017).

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