On what had been expected to be a low-key day after high scoring in the first innings, England lost six second innings wickets by mid-afternoon, when they held a precarious lead of 118.
Jonny Bairstow and Moeen Ali negotiated the rest of the afternoon and England were on 159 for six when play was called off for bad light 15 minutes after tea and abandoned 45 minutes later.
England will take a one-lead into the third Test of the four-match series, starting in Johannesburg on January 14 but South Africa will take heart from a strong fightback with both bat and ball after taking a battering in England's first innings.
The flurry of wickets on Wednesday was in complete contrast to the first four days when both teams scored more than 600 runs in their first innings and 1272 runs were scored for the loss of only 13 wickets.
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After four days of unrelenting sunshine, the sky was partly overcast on Wednesday.
The fast bowlers, led by Morne Morkel, gained some movement, while off-spinner Dane Piedt obtained some turn from a pitch which had previously offered no assistance to the bowlers.
Alastair Cook and Alex Hales fell within the first three overs of the day, both without adding to their overnight scores of eight and five respectively, while Joe Root was bowled just before the mid-morning drinks break. Nick Compton fell shortly before lunch.