What causes replication stress?
Replication stress is a complex phenomenon which has serious implications for genome stability, cell survival, and human disease. Generation of aberrant replication fork structures containing single-stranded DNA activates the replication stress response, primarily mediated by the kinase ATM- and Rad3-related (ATR).
What is oncogenic stress?
Expression of oncogenes in otherwise normal cells often leads to the activation of anti-oncogenic pathways through a poorly understood process described as ‘oncogenic stress’. A new study implicates the Jnk pathway signaling in the activation of p53 in response to both K-Ras and Neu oncogene expression.
What is the role of the CDC6 in replication?
The CDC6 gene provides instructions for making a protein that is important in the copying of a cell’s DNA before the cell divides (a process known as DNA replication). The protein produced from this gene, called cell division cycle 6 or CDC6, is one of a group of proteins known as the pre-replication complex.
How do proto-oncogenes become oncogenes?
But what types of mutations convert these proto-oncogenes into oncogenes? The answer is simple: Oncogenes arise as a result of mutations that increase the expression level or activity of a proto-oncogene.
How does stress affect DNA replication?
These stresses include, but are not limited to, DNA damage, excessive compacting of chromatin (preventing replisome access), over-expression of oncogenes, or difficult-to-replicate genome structures. Replication stress can lead to genome instability, cancer, and ageing.
What does Cdc6 and Cdt1 do?
CDC6 is an ATP binding protein and a member of the pre-replicative complex (pre-RC) together with the origin recognition complex (ORC), Cdt1 and the MCM complex (containing MCM2-7p). CDC6 assembles after ORC in an ATP dependent manner and is required for loading MCM proteins onto the DNA.
What is the function of Geminin?
Geminin is a 25 kDa nuclear protein that functions by inhibiting DNA replication. During specific phases of the cell cycle, geminin is able to bind to Cdt1 protein and inhibits pre-RC formation.
What changes cause oncogenesis?
DNA damage to specific genes can lead to the process of oncogenesis. For example, excess exposure to ionizing radiation from the sun can increase one’s risk of getting skin cancer. Exposure to DNA-damaging substances in cigarettes can increase one’s risk of lung and other cancers.
What causes DNA replication?
The initiation of DNA replication occurs in two steps. First, a so-called initiator protein unwinds a short stretch of the DNA double helix. Then, a protein known as helicase attaches to and breaks apart the hydrogen bonds between the bases on the DNA strands, thereby pulling apart the two strands.
What are the mechanisms of oncogene-induced replication stress?
Oncogene-induced replication stress is an early driver of genomic instability and is attributed to a plethora of factors, most notably aberrant origin firing, replication-transcription collisions, reactive oxygen species, and defective nucleotide metabolism.
What is the significance of replication stress in cancer?
Significance:Replication stress is a fundamental step and an early driver of tumorigenesis and has been associated with many activated oncogenes. Deciphering the mechanisms that contribute to the replication stress response may provide new avenues for targeted cancer treatment.
How is oncogene activation related to genomic instability?
Oncogene activation disturbs cellular processes and accommodates a complex landscape of changes in the genome that contribute to genomic instability, which accelerates mutation rates and promotes tumorigenesis. Part of this cellular turmoil involves deregulation of physiologic DNA replication, widel …