SUMO Works With Replication Protein A Complex to Repair DNA
ScienceDaily (Aug. 15, 2010) — A team of investigators led by a physician-scientist at The University of Texas MD Anderson Cancer Center has shown for the first time that the small protein SUMO can team up with the replication protein A (RPA) complex to facilitate DNA repair. The study is published in the Aug. 13 edition of the journalMolecular Cell.
RPA 70 is a component of multiprotein machinery called the RPA complex, which plays a crucial role in DNA replication and repair. The researchers discovered that RPA70 is associated with a SUMO-specific protease called SENP6 during a part of the cell cycle in which DNA replication occurs. They also discovered that RPA70 can be modified by SUMO, and this modification is regulated by SENP6.
"In this paper, we show the modification of RPA70 by SUMO is essential to repair DNA double-string breaks by homologous recombination," said corresponding author Edward T.H. Yeh, M.D., professor and chair of MD Anderson's Department of Cardiology. "If a mutant protein that cannot be modified by SUMO is substituted for RPA70, the cells are much more sensitive to chemotherapy and ionized radiation."
The chemotherapy drug camptothecin and ionizing radiation both attack cancer cells by causing double-strand DNA breaks. Cells respond by activating homologous recombination to repair the damage. The newly discovered connection between SUMO and RPA70 offers a potential target for short-circuiting repair, making the cells more vulnerable to treatment.
Team Has Made Multiple Discoveries
This research is one more piece in a multi-faceted puzzle Yeh and his colleagues have been working on since 1996. Yeh discovered a post-translational protein modification system that rivals ubiquitination in complexity and importance:
SUMO (small ubiquitin-related modifier) proteins, originally called Sentrin, which attach to other proteins and modify their function or physically move them within the cell (SUMOylation)
Sentrin/SUMO-specific protease (SENP), which removes SUMO from proteins (de-SUMOylation)
Mammalian cells have six SENPs, and Yeh's group is looking systematically at all of them. Their previous research has shown SENP1 enables cells to survive at low oxygen levels, which is key for development of many kinds of cancer. And, earlier this year, they reported that SENP2 plays an important part in embryonic development.
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Molecular Cell, Volume 39, Issue 3, 333-345, 13 August 2010
doi:10.1016/j.molcel.2010.07.021
Regulation of DNA Repair through DeSUMOylation and SUMOylation of Replication Protein A Complex
Hong Dou1, Chao Huang2, Melissa Singh3, 4, Phillip B. Carpenter3 and Edward T.H. Yeh1, 2, ,
1 Department of Cardiology, The University of Texas M.D. Anderson Cancer Center, The University of Texas Houston Health Science Center, Houston, TX 77030, USA
2 Texas Heart Institute/St. Luke's Episcopal Hospital, The University of Texas Houston Health Science Center, Houston, TX 77030, USA
3 Department of Biochemistry and Molecular Biology, The University of Texas Houston Health Science Center, Houston, TX 77030, USA
Corresponding author
4 Present address: Children's Cancer Hospital, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
Highlights
► SENP6 associates with RPA70 in S phase, keeping RPA70 in a hypoSUMOylated state ► DSB dissociates SENP6 from RPA70, allowing RPA70 to be modified by SUMO2/3 ► RPA70 SUMOylation facilitates the recruitment of Rad51 to initiate HR ► SUMOylation of RPA70 is important DNA repair by HR
Summary
The replication protein A complex (RPA) plays a crucial role in DNA replication and damage response. However, it is not known whether this complex is regulated by the SUMOylation pathway. Here, we show that the 70 kDa subunit of RPA (RPA70) associates with a Sentrin/SUMO-specific protease, SENP6, in the nucleus to maintain RPA70 in a hypoSUMOylated state during S phase. Campothecin (CPT), an inducer of replication stress, dissociates SENP6 from RPA70, allowing RPA70 to be modified by a small ubiquitin-like modifier 2/3 (SUMO-2/3). RPA70 SUMOylation facilitates recruitment of Rad51 to the DNA damage foci to initiate DNA repair through homologous recombination (HR). Cell lines that expressed a RPA70 mutant that cannot be SUMOylated are defective in HR and have a marked increase in sensitivity to CPT. These results demonstrate that SUMOylation status of RPA70 plays a critical role in the regulation of DNA repair through homologous recombination.
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