<P> Cyan - highlighted genes are in the microhomology - mediated end joining (MMEJ) pathway and are up - regulated in cancer . MMEJ is an additional error - prone inaccurate repair pathway for double - strand breaks . In MMEJ repair of a double - strand break, an homology of 5--25 complementary base pairs between both paired strands is sufficient to align the strands, but mismatched ends (flaps) are usually present . MMEJ removes the extra nucleotides (flaps) where strands are joined, and then ligates the strands to create an intact DNA double helix . MMEJ almost always involves at least a small deletion, so that it is a mutagenic pathway . FEN1, the flap endonuclease in MMEJ, is epigenetically increased by promoter hypomethylation and is over-expressed in the majority of cancers of the breast, prostate, stomach, neuroblastomas, pancreas, and lung . PARP1 is also over-expressed when its promoter region ETS site is epigenetically hypomethylated, and this contributes to progression to endometrial cancer, BRCA - mutated ovarian cancer, and BRCA - mutated serous ovarian cancer . Other genes in the MMEJ pathway are also over-expressed in a number of cancers (see MMEJ for summary), and are also shown in cyan . </P> <P> Differential activity of DNA repair pathways across various regions of the human genome causes mutations to be very unevenly distributed within tumor genomes . In particular, the gene - rich, early - replicating regions of the human genome exhibit lower mutation frequencies than the gene - poor, late - replicating heterochromatin . One mechanism underlying this involves the histone modification H3K36me3, which can recruit mismatch repair proteins, thereby lowering mutation rates in H3K36me3 - marked regions . Another important mechanism concerns nucleotide excision repair, which can be recruited by the transcription machinery, lowering somatic mutation rates in active genes and other open chromatin regions . </P> <P> The basic processes of DNA repair are highly conserved among both prokaryotes and eukaryotes and even among bacteriophages (viruses which infect bacteria); however, more complex organisms with more complex genomes have correspondingly more complex repair mechanisms . The ability of a large number of protein structural motifs to catalyze relevant chemical reactions has played a significant role in the elaboration of repair mechanisms during evolution . For an extremely detailed review of hypotheses relating to the evolution of DNA repair, see . </P> <P> The fossil record indicates that single - cell life began to proliferate on the planet at some point during the Precambrian period, although exactly when recognizably modern life first emerged is unclear . Nucleic acids became the sole and universal means of encoding genetic information, requiring DNA repair mechanisms that in their basic form have been inherited by all extant life forms from their common ancestor . The emergence of Earth's oxygen - rich atmosphere (known as the "oxygen catastrophe") due to photosynthetic organisms, as well as the presence of potentially damaging free radicals in the cell due to oxidative phosphorylation, necessitated the evolution of DNA repair mechanisms that act specifically to counter the types of damage induced by oxidative stress . </P>

Which of these may be a likely cause of a gross chromosomal modification