Dr. Cohen's research interests lie in the area of mammalian meiosis and gametogenesis. Using the mouse as their primary model, the Cohen lab studies the roles of various DNA repair pathways in mediating meiotic recombination events in the mouse. Focusing on the DNA mismatch repair (MMR) pathway, the Cohen lab has defined the moelcular regulation of the major crossover pathway in mammalian meiosis, the so called "ZMM" or Class I pathway in which the MMR family plays an integratl role. The lab has also helped to characterize the components of the second, class II, crossover pathway as being dependent on the MUS81 endonculease, and has begun to elucidate mechanisms by which the two pathways interact. More recently, the Cohen lab published work characterizing the role of the BLM helicase and SLX4 endonuclease in this crosstalk.
Another major focus of the lab is on the area of non-coding RNAs in gametogenesis. The Cohen lab identified a novel role for the Argonaute (AGO) 4 protein in regulating meiotic initiation and in the key events of meiotic sex chromosome inactivation (MSCI). This work has revealed, for the first time, a critical role for the AGO family within the nucleus of mammalian germ cells and indicates that these proteins function in a "RITS-like" manner to mediate silencing of unpaired chromatin.
The Cohen lab, in conjunction with Dr. Mark Roberson, is also investigating the role of ERK signaling in checkpoint control during gametogenesis. Using conditional mouse knockout strategies, this collaborative project seeks to explore how cell cycle and meiotic machineries may be linked to checkpoint control of genomic integrity during gametogenesis.
In addition to mouse models, the Cohen lab examines meiotic progression and control of recombination in a number of other mammalian models, including the dog, the Rhesus monkey, and in humans. For more information on Dr. Cohen's research, please see the Cohen Lab Website.
A new study from Andrew Grimson's lab, in collaboration with Paula Cohen's lab, has identified a key pathway required for maintenance of sex chromosome telomere integrity. Using conditional knockout mice for Dicer and Dgcr8, two key enzymes required for small RNA processing, Modzelewski et al (2015) show that loss of small RNAs during prophase I leads to telomere fusion events specifically involving the X and Y chromosomes. For further information, see the May edition of Journal of Cell Science
A recent publication by Dabaja et al (2015) has identified key cell:cell interactions that are necessary to establish normal profiles of one key microRNA, miR202-5p, in Sertoli cells. This is the first example of a germ cell regulatory interaction that is necessary for miR expression in neighboring somatic cells of the testis
The lab of Center member John Schimenti recently identified the DNA damage checkpoint pathway responsible for culling oocytes that fail to repair double stranded breaks (DSBs) that occur during meiosis or which arise in a female's oocyte pool (Bolcun-Filas et al, Science 343:533-536, 2014). Using combinations of mutants involved in recombination and DNA damage responses, they found that this pathway involves signaling of checkpoint kinase 2 (CHK2) to both p53 and p63. Disruption of this checkpoint pathway restored fertility to females that normally would be deficient of all oocytes due to defects in meiotic recombination or exposure to radiation. This discovery opens the way to using available CHK2 inhibitors to protect the oocytes of women undergoing cancer therapy that would normally cause infertility.