Biology Reference
In-Depth Information
LINE1 related mutagenesis
DNA methylation and repair
Somatic cell aging, age-associated disease
Cell death,
cancer
Cell death,
cancer
Somatic cells
Stem cells
Cell death,
cancer
Stem cell aging, age-associated disease
Figure 6.4. Model of L1 involvement in aging and age-associated diseases. A stem cell in the bottom
left corner of the diagram represents a young adult stem cell that gives rise to healthy
differentiated progeny cells. With time endogenous L1 activity most likely in the form of
L1 ORF2 expression from SpORF2 mRNA (Belancio
, 2010a,b) leads to accumula-
tion of somatic mutations (different color stars in the nucleus) that may result in
generation of differentiated progeny cells that carry those mutations, decrease in differ-
entiation potential (vertical dashed arrows), or cell death or malignant transformation.
Gradual loss of fitness or ability to perform preprogrammed functions due to accumula-
tion of mutations is reflected by the increased intensity of the gray color in the stem cells
with age. At the level of differentiated somatic cells, a healthy replicatively young cell
(the very left cell in the middle horizontal row) with time will progress into a cell (top
right corner of the diagram) that has accumulated a number of mutations in the cellular
DNA due to the endogenous L1 activity via insertional mutagenesis of full-length L1,
SINEs, and SVA elements and via integration independent mutagenic activity of L1 and
SpORF2 expression through unfaithful repair of the L1-induced DSBs (different color
stars in the nucleus). L1 activity in somatic cells may also result in cell death, cellular
senescence, or malignant transformation. An acceleration of L1-induced mutagenesis
with time may result from either increased L1 expression due to the age-associated
hypomethylation of the cellular DNA, decrease in the efficiency of the DNA repair
machinery with age, and/or age-associated alterations in the expression and/or function
of other cellular factors that may play a role in L1 expression.
et al.
