There are 7 Supplemental figures with figure legends. Figure S1. Generation of Zranb3 knockout mice; Figure S2. Loss of Smarcal1 alone does not affect replication fork stability; Figure S3. Zranb3 is not required for fork stability in the absence of Myc overexpression; Figure S4. Loss of Smarcal1 or Zranb3 does not alter B cell development in the bone marrow; Figure S5. Loss of Smarcal1 or Zranb3 does not affect the ability of bone marrow cells to differentiate into pro-B cells ex vivo; Figure S6. Overexpression of Myc combined with loss of Smarcal1 or Zranb3 does not alter B cell development in the bone marrow; Figure S7. Loss of Smarcal1 or Zranb3 does not affect pro-B cell growth.
ARTICLE ABSTRACT
The cellular DNA replication stress response functions to stabilize DNA replication forks and inhibits genome instability and tumorigenesis induced by oncogenes. However, the specific proteins required for resolving oncogenic stress remain poorly understood. Here we report that Smarcal1 and Zranb3, closely related replication fork–remodeling proteins, have nonredundant functions in resolving Myc-induced DNA replication stress. In Myc-overexpressing primary cells, significant differences in replication fork stalling, collapse, and DNA damage were detected between cells deficient in Smarcal1 or Zranb3, leading to changes in proliferation and apoptosis. These differences were also reflected in Myc-induced lymphoma development; haploinsufficiency of Smarcal1 resulted in accelerated lymphomagenesis, whereas haploinsufficiency of Zranb3 inhibited lymphoma development. Complete loss of either protein resulted in disparate survival outcomes. Our results reveal that endogenous replication stress from Myc in primary cells requires both alleles of Smarcal1 and Zranb3 and demonstrate the requirement of both proteins to stabilize replication forks upon Myc dysregulation in a nonredundant manner.
Smarcal1 and Zranb3 are essential, but nonredundant, for responding to DNA replication stress and stabilizing replication forks following Myc overexpression.See related commentary by Sotiriou and Halazonetis, p. 1297
