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RNF8-Independent Lys63 Poly-Ubiquitylation Prevents Genomic Instability in Response to Replication-Associated DNA Damage.

Ramaekers CH, van den Beucken T, Bristow RG, Chiu RK, Durocher D, Wouters BG. PLoS One. 2014 Feb 28;9(2):e89997. doi: 10.1371/journal.pone.0089997. eCollection 2014. Abstract The cellular response to DNA double strand breaks (DSBs) involves the ordered assembly of repair proteins at or near sites of damage. This process is mediated through post-translational protein modifications that include both phosphorylation and ubiquitylation. Recent ... Read More

Reprogramming metabolism with metformin improves tumor oxygenation and radiotherapy response.

Clin Cancer Res. 2013 Dec 15;19(24):6741-50. doi: 10.1158/1078-0432.CCR-13-1787. Epub 2013 Oct 18. Zannella VE1, Dal Pra A, Muaddi H, McKee TD, Stapleton S, Sykes J, Glicksman R, Chaib S, Zamiara P, Milosevic M, Wouters BG, Bristow RG, Koritzinsky M. Abstract PURPOSE: Tumor hypoxia is a negative prognostic factor in multiple cancers, due in part to its role in causing resistance to radiotherapy. Hypoxia arises in tumor regions distal ... Read More

“Two phases of disulfide bond formation have differing requirements for oxygen” J Cell Biology

Koritzinsky M, Levitin F, van den Beucken T, Rumantir RA, Harding NJ, Chu KC, Boutros PC, Braakman I, Wouters BG. J Cell Biol. 2013 Nov 18. Full text. Abstract Most proteins destined for the extracellular space require disulfide bonds for folding and stability. Disulfide bonds are introduced co- and post-translationally in endoplasmic reticulum (ER) cargo in a redox relay that requires a terminal electron acceptor. Oxygen can serve as the electron ... Read More
Hypoxic Activation of the PERK/eIF2α Arm of the Unfolded Protein Response Promotes Metastasis through Induction of LAMP3 Mujcic H, Nagelkerke A, Rouschop KM, Chung S, Chaudary N, Span PN, Clarke B, Milosevic M, Sykes J, Hill RP, Koritzinsky M, Wouters BG. Clin Cancer Res. 2013 Nov 15;19(22):6126-37. Abstract Purpose: Conditions of poor oxygenation (hypoxia) are present in many human tumors, including cervix cancer, and are associated with increased ... Read More
Contributions of AMPK and p53 dependent signaling to radiation response in the presence of metformin. Muaddi H, Chowdhury S, Vellanki R, Zamiara P, Koritzinsky M. Radiother Oncol. 2013 Jul 25. pii: S0167-8140(13)00292-2. doi: 10.1016/j.radonc.2013.06.014. [Epub ahead of print] Source Ontario Cancer Institute and Campbell Family Institute for Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada; Faculty of Medicine, ... Read More
The autophagy associated gene, ULK1, promotes tolerance to chronic and acute hypoxia. Schaaf MB, Cojocari Dan , Keulers TG, Jutten B, Starmans MH, de Jong MC, Begg AC, Savelkouls KG, Bussink J, Vooijs M, Wouters BG, Rouschop KM. Radiother Oncol. 2013 Jul 9. pii: S0167-8140(13)00293-4. doi: 10.1016/j.radonc.2013.06.015. [Epub ahead of print]Department of Radiation Oncology (Maastro Lab), GROW School for Oncology & Developmental Biology, Maastricht University Medical Center+, Maastricht, ... Read More
New small molecule inhibitors of UPR activation demonstrate that PERK, but not IRE1α signaling is essential for promoting adaptation and survival to hypoxia. Cojocari Dan, Vellanki R.N., Sit B., Uehling D., Koritzinsky M., Wouters B.G.. Abstract BACKGROUND AND PURPOSE: The unfolded protein response (UPR) is activated in response to hypoxia-induced stress in the endoplasmic reticulum (ER) and consists of three ... Read More
PERK/eIF2α signaling protects therapy resistant hypoxic cells through induction of glutathione synthesis and protection against ROS Kasper M. Rouschop, Ludwig J. Dubois, Tom G. Keulers, Twan van den Beucken, Philippe Lambin, Johan Bussink, Albert J. van der Kogel, Marianne Koritzinsky, and Bradly G. Wouters Abstract Hypoxia is a common feature of tumors and an important ... Read More