Economy Minister Zafer Caglayan and Interior Minister Muammer Guler announced their resignations just hours after Erdogan returned from a trip abroad, expected to reshuffle his cabinet.
The sons of both ministers are among the two dozen people who have been charged as part of a high-level bribery and corruption probe that has hit Erdogan with the biggest challenge yet to his 11 years in power.
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He has responded to the investigation by sacking dozens of police chiefs.
Caglayan kept up the government's defiance in Wednesday's resignation statement, declaring that the investigation was "clearly a hideous plot against our government, our party and our country."
"I am stepping down from my post as economy minister so that this ugly game targeting my close colleagues and my son will be spoiled and the truth will be revealed," Caglayan said.
Guler, the interior minister, simply told the state-run Anatolia news agency that "I offered my resignation to the prime minister on December 17 and today I conveyed it in writing."
The fast-moving police enquiry has struck at the heart of Turkey's ruling political elite, including sons of government ministers and businessmen, and has thrown up a serious challenge for Erdogan's Justice and Development Party (AKP), which already weathered mass street protests in June.
Observers say the wide-ranging investigation has exposed a rift between Erdogan's Justice and Development Party (AKP) government and Fethullah Gulen, a hugely influential Muslim cleric who lives in the United States and whose movement wields considerable influence in Turkey's police and judiciary.
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