Fig. 1 |. Illustration of causes of replication stress.

A replication fork consists of an enzyme with helicase activity (shown in yellow) and an enzyme with polymerase activity (shown in blue). Replicative stress results from endogenous or exogenous obstacles to DNA replication. The red arrows indicate the direction of the continuous DNA synthesis on the leading strand and the blue arrows indicate the direction of the non-continuous DNA synthesis on the lagging strand. Oncogenic activation and some chemotherapeutic agents such as gemcitabine cause depletion of deoxynucleotides (dNTPs), which impairs the progression of ongoing DNA replication. Increased origin firing (shown by pink circles labelled with the letter F) may be caused by oncogenic activation or loss of tumour suppressor genes. Different types of DNA damage caused by endogenous and exogenous agents lead to replication stress if left unrepaired. Repetitive DNA sequence, rehybridization of the nascent RNA to DNA, forming R-loops, misincorporation of ribonucleotides and secondary DNA structures such as hairpins and quadruplexes pose a challenge to DNA replication and are endogenous causes of replication stress even in healthy cells. Finally, collisions between replication and transcription machinery result in replication stress. RNA polymerase is shown as the blue protein and the newly synthesized RNA molecule is shown in purple.