A new study from Sidney Kimmel Cancer Center – Jefferson Health (SKCC) researchers provides important insights into the role of DNA replication fork remodeling in mitigating stress on DNA caused by dysregulation of the Myc oncogene, which occurs in at least 70 percent of human cancers. The study was published in the journal Cancer Research.
Senior author Christine M. Eischen, PhD, Co-leader of the Molecular Biology and Genetics Program at SKCC and Herbert A. Rosenthal, MD ’56 Professor in Cancer Research, and colleagues studied the role of two closely related proteins, termed Smarcal1 and Zranb3, which stabilize stalled DNA replication forks, a structural feature of chromosomes in actively dividing cells. When a cell divides, it must duplicate its chromosomes so that a full set is passed on to each of the two daughter cells and DNA replication forks do this. When problems occur during DNA duplication, specialized proteins involved in the “DNA replication stress response” are called to the site to protect against DNA replication fork collapse and DNA damage that can lead to cell death or mutations that can result in cancer.
The SKCC investigators discovered that during lymphoma development induced by the Myc oncogene, Smarcal1 and Zranb3 have non-redundant critical roles in resolving DNA replication stress and are unable to functionally compensate for one another. The new study is the first to directly compare the in vivo functions of these two closely related DNA replication stress response proteins, and it demonstrates that Myc-overexpressing cells lacking either protein exhibit significant differences in replication fork stalling, collapse, and DNA damage, thereby leading to changes in cell proliferation and cell death. These effects were linked to altered B-cell lymphoma development.
“We have identified replication stress-induced by Myc as the first endogenous source of DNA replication stress that requires both proteins for resolution,” Eischen explained. “Our data greatly enhance understanding of the DNA replication stress response and the essential functions two fork remodeling proteins have in protecting cells from the early stages of cancer development.”
These findings also have potential implications for the clinical development of new cancer treatment strategies. With regard to Smarcal1 and Zranb3, Eischen points out that “due to their critical roles in mitigating DNA replication stress caused by an oncogene, targeting one or both of these proteins could be considered for some types of cancer.”
The Eischen laboratory is actively following up on this research by investigating the role of these two proteins in hematopoiesis and immune cell deficiencies that contribute to lymphoma susceptibility. It is anticipated that these studies will contribute to our understanding of the cellular events underlying lymphoma development and will eventually lead to more effective treatments for this class of deadly tumors.
Read the related commentary published in Cancer Research from Sotirios K. Sotirious and Thanos D. Halazonetis: Remodeling Collapsed DNA Replication Forks for Cancer Development.
Article reference: Puccetti MV, Adams CM, Kushinsky S, and Eischen CM. Smarcal1 and Zranb3 protect replication forks from Myc-induced DNA replication stress. Cancer Research, DOI: 10.1158/0008-5472.CAN-18-2705.