GADD34Growth Arrest and DNA Damage Protein 34
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To validate RRBS candidates, we used either pyrosequencing or bisulfite amplicon sequencing (BSAS) of SM-DMRs in or near ALPPL2, AHRR, PPP1R15A (GADD34), SLC24A3, AHRR-C5orf55-EXOC-AS, F2RL3-DMR1, F2RL3-CPAMD8DMR2, HOXA5, SASH1, RDX, and LRP5 and on monocyte DNA from a larger group of 85 CRU-Pyro subjects that included the 38 CRU-RRBS subjects (Table 1; see also Excel Table S1).
It is notable that a number of the DMR genes, including AHRR, F2RL3, HOXA5, SASH1, LRP5, and PPP1R15A (GADD34) have been associated with cardiovascular diseases/atherosclerosis either through nearby DNA methylation and/or gene expression (listed in Table 2).
(A-C, G-I) Selected candidate SM-DMRs (A) ALPPL2, (B) PPP1R15A (GADD34), (C) SLC24A4, (G) AHRR-C5orf55-EXOC-AS, (H) F2RL3, F2RL3-CPAMD8, and (I) LRP5 that displayed significant, smoking-associated methylation differences by pyrosequencing of monocyte DNA from CRU-Pyro group described in Methods.
Wu et al., "Leukemic HRX fusion proteins inhibit GADD34-induced apoptosis and associate with the GADD34 and hSNF5/INI1 proteins," Molecular and Cellular Biology, vol.
GADD34's dephosphorylation activity is required to recommence protein synthesis after periods of global translation inhibition.
5MP promotes expression of GADD34 (a downstream target of ATF4) in Tribolium castaneum [169].
Upregulation of CHOP can also induce the expression of Ero1[alpha] and GADD34 [22-26], Ero1[alpha] can trigger apoptosis directly, and GADD34 can further make P-eIF2[alpha] (function is slowing down or even suspending misfolded proteins synthesis) dephosphorylated and then result in misfolded proteins synthesis conduct.
Caption: Figure 4: TLN can decrease the expression of GADD34 and Ero1[alpha] and increase the expression of P- eIF2[alpha] in high glucose-induced RSC96 cells.
In addition, guanabenz selectively inhibits stress-induced dephosphorylation of eIF2[alpha] by the GADD34:PP1 complex, without affecting the activity of the constitutively activated CReP:PP1 complex (Figure 2) [41].
Sephin1 is a guanabenz derivative with selective inhibitory effect on stress-induced dephosphorylation of eIF2[alpha] by the GADD34:PP1 complex (Figure 2), without [alpha]2-adrenergic activity [42].
ATF4, a crucial transcription factor, which is induced by PERK-mediation of phosphorylation of eIF2[alpha]; and activates pro-apoptotic factor CFIOP and GADD34 (Fian et al.
It is worth mentioning that CHOP induced GADD34 expression, which regulates restoration of protein synthesis via a negative feedback loop by dephosphorylation of eIF-2[alpha].