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  • ALG-2/AGO-Dependent mir-35 Family Regulates DNA Damage-Induced Apoptosis Through MPK-1/ERK MAPK Signaling Downstream of the Core Apoptotic Machinery in Caenorhabditis elegans.

ALG-2/AGO-Dependent mir-35 Family Regulates DNA Damage-Induced Apoptosis Through MPK-1/ERK MAPK Signaling Downstream of the Core Apoptotic Machinery in Caenorhabditis elegans.

Genetics (2019-07-13)
Markus Alexander Doll, Najmeh Soltanmohammadi, Björn Schumacher
ABSTRACT

MicroRNAs (miRNAs) associate with argonaute (AGO) proteins to post-transcriptionally modulate the expression of genes involved in various cellular processes. Herein, we show that loss of the Caenorhabditis elegans AGO gene alg-2 results in rapid and significantly increased germ cell apoptosis in response to DNA damage inflicted by ionizing radiation (IR). We demonstrate that the abnormal apoptosis phenotype in alg-2 mutant animals can be explained by reduced expression of mir-35 miRNA family members. We show that the increased apoptosis levels in IR-treated alg-2 or mir-35 family mutants depend on a transient hyperactivation of the C. elegans ERK1/2 MAPK ortholog MPK-1 in dying germ cells. Unexpectedly, MPK-1 phosphorylation occurs downstream of caspase activation and depends at least in part on a functional cell corpse-engulfment machinery. Therefore, we propose a refined mechanism, in which an initial proapoptotic stimulus by the core apoptotic machinery initiates the engulfment process, which in turn activates MAPK signaling to facilitate the demise of genomically compromised germ cells.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Acridine Orange hydrochloride solution, 10 mg/mL in H2O
Sigma-Aldrich
Anti-HA antibody produced in rabbit, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
Anti-MAP Kinase, Activated (Diphosphorylated ERK-1&2) antibody, Mouse monoclonal, clone MAPK-YT, purified from hybridoma cell culture