The process of genome instability often leads to a situation of aneuploidy, in which the cells present a chromosomic number that is either higher or lower than the normal complement for the species.
The replisome must be able to navigate obstacles such as tightly wound chromatin with bound proteins, single and double stranded breaks which can lead to the stalling of the replication fork.
[5] Proteins such as Tel1 and Mec1 (ATR, ATM in humans) can detect single and double-stranded breaks and recruit factors such as Rmr3 helicase to stabilize the replication fork in order to prevent its collapse.
These proteins also prevent progression into mitosis by inhibiting the firing of late replication origins until the DNA breaks are fixed by phosphorylating CHK1 and CHK2, which results in a signaling cascade arresting the cell in S-phase.
An example is the Saccharomyces pombe gene rad9 which arrests the cells in late S/G2 phase in the presence of DNA damage caused by radiation.
The cells that arrested were able to survive due to the increased time in S/G2 phase allowing for DNA repair enzymes to function fully.
Using a sister chromatid as repair is not a fool-proof backup as the surrounding DNA information of the n and n+1 repeat is virtually the same, leading to copy number variation.
[citation needed] In both E. coli and Saccharomyces pombe, transcription sites tend to have higher recombination and mutation rates.
In S. cerevisiae, Rrm3 helicase is found at highly transcribed genes in the yeast genome, which is recruited to stabilize a stalling replication fork as described above.
In yeast, proteins act as barriers at the 3' of the transcription unit to prevent further travel of the DNA replication fork.
During development of the B cell, a specific V, D, and J segment is chosen to be spliced together to form the final gene, which is catalyzed by RAG1 and RAG2 recombinases.
Uracil normally does not exist in DNA, and thus the base is excised and the nick is converted into a double-stranded break which is repaired by non-homologous end joining (NHEJ).
[12] Of about 200 neurological and neuromuscular disorders, 15 have a clear link to an inherited or acquired defect in one of the DNA repair pathways or excessive genotoxic oxidative stress.
Four (ataxia-telangiectasia, ataxia-telangiectasia-like disorder, Nijmegen breakage syndrome and Alzheimer's disease) are defective in genes involved in repairing DNA double-strand breaks.
[citation needed] It is currently accepted that sporadic tumors (non-familial ones) are originated due to the accumulation of several genetic errors.
[citation needed] For example, in the case of lung cancer, DNA damage is caused by agents in exogenous genotoxic tobacco smoke (e.g. acrolein, formaldehyde, acrylonitrile, 1,3-butadiene, acetaldehyde, ethylene oxide and isoprene).
The average number of DNA sequence mutations in the entire genome of a breast cancer tissue sample is about 20,000.
[30] The high frequency of mutations in the total genome within cancers suggests that, often, an early carcinogenic alteration may be a deficiency in DNA repair.
In addition, faulty repair of these accumulated DNA damages may give rise to epigenetic alterations or epimutations.
Two or three epigenetic deficiencies in expression of ERCC1, XPF and/or PMS2 were found to occur simultaneously in the majority of the 49 colon cancers evaluated.
Many types of lymphoma are caused by chromosomal translocation, which can arise from breaks in DNA, leading to incorrect joining.
Follicular lymphoma results from the translocation of the immunoglobulin promoter to the Bcl-2 gene, giving rise to high levels of Bcl-2 protein, which inhibits apoptosis.