Much of the current effort in cancer biology is concentrated on studying either the cell growth and proliferation or the programmed cell death (apoptosis) pathways individually, and little is known about the coregulation of these two vital processes. Understanding processes and controls common to both cell proliferation and apoptosis would provide a new paradigm for identifying novel targets in the treatment of hematologic malignancies and other cancers. We propose that the processes of mitotic segregation and apoptosis are mechanistically linked and that proteins important for sister chromatid cohesion play a role in regulating normal apoptotic processes. Deregulation of this joint process can lead to formation and progression of hematologic cancers and development of therapy-resistant leukemia and lymphoma. Cohesin Rad21, a mitotic regulatory protein may play an important role in the interface between cell proliferation and apoptosis. Rad21 functions in chromosome segregation and DMAdamage repair during cell proliferation but promotes cell death once apoptosis is induced. Our lab is one of two laboratories that have recently identified a novel role for Rad21 in apoptosis. To test the central hypothesis that mitotic segregation and apoptosis are linked processes, we will focus on specific roles of the cohesin protein Rad21 in apoptosis.
Our aims are (a) to identify the nuclear protease that cleaves Rad21 in the nucleus at the early stage of apoptosis induction and to elucidate its role in Rad21 -mediated apoptosis, (b) to identify proteins interacting with C-terminal Rad21 in the apoptotic pathway, and (c) to determine the pathways through which C-terminal Rad21 amplifies apoptotic signals and activates effector caspases in leukemia cell lines. The series of studies proposed will provide novel information about how mitotic proteins regulate apoptosis and their role in carcinogenesis. Understanding the details of cohesin cleavage and subsequent steps in the apoptotic cascade in leukemic cells is expected to lead to the identification of novel targets and strategies for the treatment of hematologic cancers. Furthermore, identification of the mechanism through which C- terminal Rad21 promotes programmed cell death will help explain why leukemic cells are able to evade and resist apoptosis and will aid the design of new strategies for treating chemotherapy-resistant leukemia.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Hematopoiesis Study Section (HP)
Program Officer
Mufson, R Allan
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Baylor College of Medicine
Schools of Medicine
United States
Zip Code
Zhang, Nenggang; Pati, Debananda (2015) C-terminus of Sororin interacts with SA2 and regulates sister chromatid cohesion. Cell Cycle 14:820-6
Chen, Yulong; Terajima, Masahiko; Yang, Yanan et al. (2015) Lysyl hydroxylase 2 induces a collagen cross-link switch in tumor stroma. J Clin Invest 125:1147-62
Shete, Amol; Rao, Pulivarthi; Pati, Debananda et al. (2014) Spatial quantitation of FISH signals in diploid versus aneuploid nuclei. Cytometry A 85:339-52
Mukherjee, Malini; Byrd, Tiara; Brawley, Vita S et al. (2014) Overexpression and constitutive nuclear localization of cohesin protease Separase protein correlates with high incidence of relapse and reduced overall survival in glioblastoma multiforme. J Neurooncol 119:27-35
Mukherjee, M; Ge, G; Zhang, N et al. (2014) MMTV-Espl1 transgenic mice develop aneuploid, estrogen receptor alpha (ER*)-positive mammary adenocarcinomas. Oncogene 33:5511-22
Zhang, Nenggang; Jiang, Yunyun; Mao, Qilong et al. (2013) Characterization of the interaction between the cohesin subunits Rad21 and SA1/2. PLoS One 8:e69458
Zhang, Nenggang; Pati, Debananda (2012) Sororin is a master regulator of sister chromatid cohesion and separation. Cell Cycle 11:2073-83
Panigrahi, Anil K; Zhang, Nenggang; Otta, Subhendu K et al. (2012) A cohesin-RAD21 interactome. Biochem J 442:661-70
Panigrahi, Anil K; Pati, Debananda (2012) Higher-order orchestration of hematopoiesis: is cohesin a new player? Exp Hematol 40:967-73
Panigrahi, Anil K; Zhang, Nenggang; Mao, Qilong et al. (2011) Calpain-1 cleaves Rad21 to promote sister chromatid separation. Mol Cell Biol 31:4335-47

Showing the most recent 10 out of 17 publications