DNA Damage as a Driver for Growth Delay: Chromosome Instability Syndromes with Intrauterine Growth Retardation

Figure 2

DNA damage response can result in different outcomes following single strand breaks, interstrand crosslinks and double strand breaks. Each DNA lesion is recognized by specific sensor proteins according to the cell cycle phase in which the cell is; during S phase, the protein FANCM identifies a replication fork arrested by an ICL, MRN + BRCA1 sense DSBs; meanwhile, Ku70/Ku80 + 53BP1 can recognize DSBs across the entire interphase; RPA detects and covers ssDNA primarily during S phase. The sensing process is then transduced and amplified on chromatin through a series of posttranslational histone modifications such as phosphorylation of H2AX (γH2AX) on both sides of the DSB. These changes allow the recruitment of the specialized transducer kinase ATR that mainly responds to RPA-covered ssDNA originated by replication stress or DNA lesions such as ICLs; concurrently, ATM responds to DSBs. Kinases activate several effector proteins including the transcription factor p53, which acts downstream regulating diverse outcomes according to the type and quantity of reminding lesions in the cell.