Noncanonical roles for RNA in maintaining genomic stability and influencing organismal physiology
- Author(s): Asundi, Aarati
- Advisor(s): Blelloch, Robert
- et al.
It is becoming increasingly clear that sensory neurons are able to integrate information about environmental changes to regulate aspects of an organism’s physiology. The L’Etoile lab has gathered evidence suggesting that mobile small RNAs may represent a previously unidentified endocrine signal and thus, might regulate various physiological outputs. My thesis work used different models and experimental approaches to test the hypothesis that small RNA machinery acts as a regulator of mitotic signals to ensure genomic integrity in proliferative cell populations. The proliferative germ cells (PGCs) in the C. elegans nematode and MCF10As, a human derived, non-tumorgenic breast epithelial cell line, are complementary models that are ideal to study how the small RNA pathway might regulate mitosis.
I discovered that loss of NRDE2, a nuclear RNAi-dependent protein, induces DNA damage accumulation specifically under conditions of stress, such as high cultivation temperature in C. elegans or Aurora B Kinase oncogenic overexpression in MCF10A cells. I found that NRDE2 interacts with β-actin in unstressed mammalian cells. This interaction is dramatically reduced upon DNA damage and increased in the absence of RNA. I propose a model by which NRDE2 associates with actin only when DNA is intact and the bulk of nuclear actin is monomeric. Thus, NRDE2 may dissociate from actin when it becomes filamentous as a result of DNA damage. This implies that, NRDE2, in its role as a heterochromatin factor, binds to monomeric actin, protecting the genome from DNA damage in stressful conditions.
I have also gathered preliminary data showing that the AWC olfactory sensory neurons are required to regulate brood size and egg laying pattern in C. elegans. Furthermore, my preliminary evidence indicates that SID-1, an import channel required for RNAi spreading, is required to regulate brood size and germ cell proliferation. This suggests that mobile RNAs could act as hormones to allow for gene specific regulation of distant target cells, providing a novel pathway for scientists to understand regulation of cell-cell communication and the subsequent consequences of its dysfunction.
This thesis work lays groundwork for further studies into small RNAs as regulators for epigenetic inheritance, cancer, reproduction and mental health.