When Escherichia coli grows in the presence of DNA-damaging agents such as methyl methanesulphonate (MMS), absence of the full-length form of Translation Initiation Factor 2 (IF2-1) or deficiency in helicase activity of replication restart protein PriA leads to a considerable loss of viability. MMS sensitivity of these mutants was contingent on the stringent response alarmone (p)ppGpp being at low levels. While zero levels (ppGpp0) greatly aggravated sensitivity, high levels promoted resistance. Moreover, M+ mutations, which suppress amino acid auxotrophy of ppGpp0 strains and which have been found to map to RNA polymerase subunits, largely restored resistance to IF2-1- and PriA helicase-deficient mutants. The truncated forms IF2-2/3 played a key part in inducing especially severe negative effects in ppGpp0 cells when restart function priB was knocked out, causing loss of viability and severe cell filamentation, indicative of SOS induction. Even a strain with the wild-type infB allele exhibited significant filamentation and MMS sensitivity in this background whereas mutations that prevent expression of IF2-2/3 essentially eliminated filamentation and largely restored MMS resistance. The results suggest different influences of IF2-1 and IF2-2/3 on the replication restart system depending on (p)ppGpp levels, each having the capacity to maximize survival under differing growth conditions.