Tongyuan Li

Human DDX11 and DDX12 are closely related genes encoding the helicases ChlR1 and ChlR2, which belong to the CHL1 DNA helicase family. Recently, it was shown that human ChlR1 interacts with components of the cohesin complex and is required for proper centromeric cohesion. To establish the function of ChlR1 in development we made a mutant mouse lacking Ddx11, the single mouse ChlR gene. The absence of Ddx11 resulted in embryonic lethality at E10.5. The mutant embryos were smaller in size, malformed and exhibited sparse cellularity in comparison to normal or heterozygous litter mates. Importantly, loss of Ddx11 resulted in the inability to form a proper placenta, indicating that ChlR1 is essential for placental formation. Detailed analysis of cells isolated from Ddx11-/- embryos revealed a G2/M cell cycle delay, an increased frequency of chromosome missegregation, decreased chromosome cohesion, and increased aneuploidy. To examine whether ChlR proteins are required for arm cohesion and for loading of the cohesin complex, further studies were preformed in ChlR1 siRNA treated cells. These studies revealed that ChlR1 is required for proper sister chromatid arm cohesion and that cohesin complexes bind more loosely to chromatin in the absence of ChlR1. Taken together, these studies provide the first data indicating that the ChlR1 helicase is essential for proper binding of the cohesin complex to both the centromere and the chromosome arms, and indicate that ChlR1 is essential for embryonic development and the prevention of aneuploidy in mammals.

// Tongyuan Li 1,2 , Xiangyu Liu 1,2 , Le Jiang 1,2 , James Manfredi 3 , Shan Zha 1,2,4 and Wei Gu 1,2 1 Institute for Cancer Genetics, and Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA 2 Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA 3 Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA 4 Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY, USA Correspondence to: Wei Gu, email: // Keywords : p53, acetylation, ferroptosis, tumor suppression, genomic instability Received : January 15, 2016 Accepted: February 18, 2016 Published: March 02, 2016 Abstract Although p53-mediated cell cycle arrest, senescence and apoptosis are well accepted as major tumor suppression mechanisms, the loss of these functions does not directly lead to tumorigenesis, suggesting that the precise roles of these canonical activities of p53 need to be redefined. Here, we report that the cells derived from the mutant mice expressing p53 3KR , an acetylation-defective mutant that fails to induce cell-cycle arrest, senescence and apoptosis, exhibit high levels of aneuploidy upon DNA damage. Moreover, the embryonic lethality caused by the deficiency of XRCC4, a key DNA double strand break repair factor, can be fully rescued in the p53 3KR/3KR background. Notably, despite high levels of genomic instability, p53 3KR/3KR XRCC4 -/- mice, unlike p53 -/- XRCC4 -/- mice, are not succumbed to pro-B-cell lymphomas. Nevertheless, p53 3KR/3KR XRCC4 -/- mice display aging-like phenotypes including testicular atrophy, kyphosis, and premature death. Further analyses demonstrate that SLC7A11 is downregulated and that p53-mediated ferroptosis is significantly induced in spleens and testis of p53 3KR/3KR XRCC4 -/- mice. These results demonstrate that the direct role of p53-mediated cell cycle arrest, senescence and apoptosis is to control genomic stability in vivo . Our study not only validates the importance of ferroptosis in p53-mediated tumor suppression in vivo but also reveals that the combination of genomic instability and activation of ferroptosis may promote aging-associated phenotypes.