Biology Reference
In-Depth Information
The same assumption is true for a long list of cellular processes, ranging from
DNA methylation, transcription, and RNA processing to antiviral defense,
reported to control various steps of the L1 life cycle. The existence of these
additional dimensions influencing potential L1-associated health risk suggests a
scenario under which individuals with the same cumulative endogenous L1
activity may endure drastically different burden from the L1-induced DNA
damage. On the other hand, persons with relatively low endogenous L1 activity
may have comparable load of the L1-associated mutagenesis to individuals with
significantly higher endogenous L1 activity depending on the strength of their
anti-TE shield. Thus, the consideration of the status of all the players of the TE-
controlling network is necessary for the proper assessment of the TE-associated
individual health risk and further thorough evaluation of the complex relation-
ship between TEs and their hosts need to take place.
Inherited defects in any of the pathways controlling TE expression and/
or activity would result in systemic or tissue- or development-specific increase in
the TE-associated damage, while acquired somatic mutations are likely to be
limited to the cells in which they occurred. Even though little is known about
the combined effect of L1 activity with either somatic or germline mutations, it
can potentially be a significant contributor to human diseases. For example, high
risk of breast cancer associated with inactivating BRCA1 mutations is proposed
to be linked the mutagenic repair of DSBs induced by response to estrogen (Fu
et al.
, 2003). Despite the fact that L1 expression and the role of the L1-induced
DSBs in mammary gland tumorigenesis remain unexplored, it may be one of the
factors contributing to genomic instability during breast cancer development.
A. The potential for L1 to contribute to cancer and aging
The finding of extensive endogenous L1 expression in normal human somatic
tissues combined with the L1's ability to induce DSBs not only in human cancer
but also normal cells brings a possibility that ongoing endogenous L1 expression
can be a continuous source of DNA damage in somatic tissues (Belancio
,
2010b). DNA damage is known to promote genomic instability, which is one of
the contributing factors of the normal aging process and age-associated diseases
particularly cancer (Campisi and Vijg, 2009; Coppede and Migliore, 2010; Erol,
2010). One of the accepted theories of mammalian aging is destabilization of the
genome through accumulation of DNA damage over the course of life span of an
organism (Alexander, 1967). Low levels of endogenous L1 expression in the
majority of human somatic tissues and adult stem cells strongly suggests that
ongoing L1 expression can contribute to genomic instability over the life span of
an organism through retrotransposition of L1, SINEs, and SVA elements, re-
combination between interspersed copies of L1 and SINEs, and DNA DSBs
induced by L1 EN. Endogenous L1 expression varies significantly among
et al.
