Dynamic changes in ORC localization and replication fork progression during tissue differentiation

Details

• Alternative Title:
  BMC Genomics
• Personal Author:
  Hua, Brian L. ; Bell, George W. ; Kashevsky, Helena ; Von Stetina, Jessica R. ; Orr-Weaver, Terry L.
• Description:
  Background
  
  Genomic regions repressed for DNA replication, resulting in either delayed replication in S phase or underreplication in polyploid cells, are thought to be controlled by inhibition of replication origin activation. Studies in Drosophila polytene cells, however, raised the possibility that impeding replication fork progression also plays a major role.
  
  Results
  
  We exploited genomic regions underreplicated (URs) with tissue specificity in Drosophila polytene cells to analyze mechanisms of replication repression. By localizing the Origin Recognition Complex (ORC) in the genome of the larval fat body and comparing this to ORC binding in the salivary gland, we found that sites of ORC binding show extensive tissue specificity. In contrast, there are common domains nearly devoid of ORC in the salivary gland and fat body that also have reduced density of ORC binding sites in diploid cells. Strikingly, domains lacking ORC can still be replicated in some polytene tissues, showing absence of ORC and origins is insufficient to repress replication. Analysis of the width and location of the URs with respect to ORC position indicates that whether or not a genomic region lacking ORC is replicated is controlled by whether replication forks formed outside the region are inhibited.
  
  Conclusions
  
  These studies demonstrate that inhibition of replication fork progression can block replication across genomic regions that constitutively lack ORC. Replication fork progression can be inhibited in both tissue-specific and genome region-specific ways. Consequently, when evaluating sources of genome instability it is important to consider altered control of replication forks in response to differentiation.
  
  Electronic supplementary material
  
  The online version of this article (10.1186/s12864-018-4992-3) contains supplementary material, which is available to authorized users.
  
  
• Subjects:
  Common Fragile Sites DNA Replication Drosophila Research Article Transcription
• Source:
  BMC Genomics. 19.
• Pubmed ID:
  30134926
• Pubmed Central ID:
  PMC6103881
• Document Type:
  Journal Article
• Funding:
  HG004279/National Human Genome Research Institute/ ; U01 HG004279/HG/NHGRI NIH HHS/United States ; GM118098/National Institute of General Medical Sciences/ ; GM57940/National Institute of General Medical Sciences/ ; R35 GM118098/GM/NIGMS NIH HHS/United States
• Volume:
  19
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:86d2c732cbe47f3fd5e6b92ae5408f08f2b881d09be02ca6ddd1310a8d97f311
• Download URL:
  https://stacks.cdc.gov/view/cdc/59260/cdc_59260_DS1.pdf
• File Type:
  [PDF - 2.03 MB ]